Pyrazinones and triazinones and their derivatives thereof

ABSTRACT

Corticotropin releasing factor (CRF) antagonists of Formula (I) ##STR1## and their use in treating psychiatric disorders and neurological diseases including major depression, anxiety-related disorders, post-traumatic stress disorders, supranuclear palsy and eating disorders.

This application claims the benefit of U.S. Provisional Application No. 60/026,373, filed Sep. 16, 1996.

FIELD OF THE INVENTION

This invention relates to novel compounds and pharmaceutical compositions, and to methods of using same in the treatment of psychiatric disorders and neurological diseases including major depression, anxiety-related disorders, post-traumatic stress disorders, supranuclear palsy and eating disorders.

BACKGROUND OF THE INVENTION

Corticotropin releasing factor (herein referred to as CRF), a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin(POMC)-derived peptide secretion from the anterior pituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)]. In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in brain [W. Vale et al., Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39 (1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There is also evidence that CRF plays a significant role in integrating the response of the immune system to physiological, psychological, and immunological stressors [J. E. Blalock, Physiological Reviews 69:1 (1989); J. E. Morley, Life Sci. 41:527 (1987)].

Clinical data provide evidence that CRF has a role in psychiatric disorders and neurological diseases including depression, anxiety-related disorders and eating disorders. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, progressive supranuclear palsy and amyotrophic lateral sclerosis as they relate to the dysfunction of CRF neurons in the central nervous system [for review see E. B. De Souza, Hosp. Practice 23:59 (1988)].

In affective disorder, or major depression, the concentration of CRF is significantly increased in the cerebral spinal fluid (CSF) of drug-free individuals [C. B. Nemeroff et al., Science 226:1342 (1984); C. M. Banki et al., Am. J. Psychiatry 144:873 (1987); R. D. France et al., Biol. Psychiatry 28:86 (1988); M. Arato et al., Biol Psychiatry 25:355 (1989)]. Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF [C. B. Nemeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. In addition, there is a blunted adrenocorticotropin (ACTH) response to CRF (i.v. administered) observed in depressed patients [P. W. Gold et al., Am J. Psychiatry 141:619 (1984); F. Holsboer et al., Psychoneuroendocrinology 9:147 (1984); P. W. Gold et al., New Eng. J. Med. 314:1129 (1986)]. Preclinical studies in rats and non-human primates provide additional support for the hypothesis that hypersecretion of CRF may be involved in the symptoms seen in human depression [R. M. Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)]. There is preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate the numbers of CRF receptors in brain [Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)].

There has also been a role postulated for CRF in the etiology of anxiety-related disorders. CRF produces anxiogenic effects in animals and interactions between benzodiazepine/non-benzodiazepine anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety models [D. R. Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J. Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using the putative CRF receptor antagonist a-helical ovine CRF (9-41) in a variety of behavioral paradigms demonstrate that the antagonist produces "anxiolytic-like" effects that are qualitatively similar to the benzodiazepines [C. W. Berridge and A. J. Dunn Horm. Behav. 21:393 (1987), Brain Research Reviews 15:71 (1990)]. Neurochemical, endocrine and receptor binding studies have all demonstrated interactions between CRF and benzodiazepine anxiolytics providing further evidence for the involvement of CRF in these disorders. Chlordiazepoxide attenuates the "anxiogenic" effects of CRF in both the conflict test [K. T. Britton et al., Psychopharmacology 86:170 (1985); K. T. Britton et al., Psychopharmacology 94:306 (1988)] and in the acoustic startle test [N. R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats. The benzodiazepine receptor antagonist (Ro15-1788), which was without behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dose-dependent manner while the benzodiazepine inverse agonist (FG7142) enhanced the actions of CRF [K. T. Britton et al., Psychopharmacology 94:306 (1988)].

The mechanisms and sites of action through which the standard anxiolytics and antidepressants produce their therapeutic effects remain to be elucidated. It has been hypothesized however, that they are involved in the suppression of the CRF hypersecretion that is observed in these disorders. Of particular interest is that preliminary studies examining the effects of a CRF receptor antagonist (a-helical CRF₉₋₄₁) in a variety of behavioral paradigms have demonstrated that the CRF antagonist produces "anxiolytic-like" effects qualitatively similar to the benzodiazepines [for review see G. F. Koob and K. T. Britton, In: Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E. B. De Souza and C. B. Nemeroff eds., CRC Press p221 (1990)].

DuPont Merck PCT application WO95/10506 describes corticotropin releasing factor antagonist compounds and their use to treat psychiatric disorders and neurological diseases.

European patent application 0 576 350 A1 by Elf Sanofi describes corticotropin releasing factor antagonist compounds useful in the treatment of CNS and stress disorders.

Pfizer patent applications WO 94/13676, WO 94/13677, WO 94/13661, WO 95/33750, WO 95/34563, WO 95/33727 describe corticotropin releasing factor antagonist compounds useful in the treatment of CNS and stress disorders.

All of the aforementioned references are hereby incorporated by reference.

The compounds and the methods of the present invention provide for the production of compounds capable of inhibiting the action of CRF at its receptor protein in the brain. These compounds would be useful in the treatment of a variety of neurodegenerative, neuropsychiatric and stress-related disorders such as affective disorders, anxiety, depression, post-traumatic stress disorders, supranuclear palsy, seizure disorders, stroke, irritable bowel syndrome, immune suppression, Alzheimer's disease, gastrointestinal disease, anorexia nervosa or other eating disorders, drug or alcohol withdrawal symptoms, drug addiction, inflammatory disorders and fertility problems. It is further asserted that this invention may provide compounds and pharmaceutical compositions suitable for use in such a method.

SUMMARY OF THE INVENTION

This invention is a class of novel compounds which are CRF receptor antagonists and which can be represented by Formula (I): ##STR2## or a pharmaceutically acceptable salt form thereof, wherein Z is CR² or N;

when Z is CR² :

Y is NR⁴, O or S(O)_(n) ;

Ar is phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, indolinyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, benzothiazolyl, indazolyl, isoxazolyl or pyrazolyl, each substituted with 0 to 4 R⁵ groups; wherein Ar is attached to Y through an unsaturated carbon;

R¹ is H, halo, C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₃ -C₈ cycloalkyl, C₁ -C₄ haloalkyl, aryl, heterocyclyl, --CN, --OR⁷, --SH, --S(O)_(n) R¹³, --COR⁷, --CONR⁶ R⁷, --CO₂ R⁷, --OC(O)R¹³, --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R⁷, or --NR⁶ R⁷, wherein C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl or C₃ -C₈ cycloalkyl is each substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, --CN, --OR⁷, --SH, --S(O)_(n) R¹³, --COR⁷, --CO₂ R⁷, --OC(O)R¹³, --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R⁷, --NR⁶ R⁷, --CONR⁶ R⁷, aryl and heterocyclyl;

R² is H, C₁ -C₄ alkyl, C₂ -C₄ alkenyl, C₂ -C₄ alkynyl, C₃ -C₆ cycloalkyl, halo, --CN, C₁ -C₄ haloalkyl, --NR⁹ R¹⁰, --NR⁹ COR¹⁰, --NR⁹ CO₂ R¹⁰, --OR¹¹, --SH or --S(O)_(n) R¹² ;

R³ is C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₃ -C₈ cycloalkyl, C₁ -C₄ haloalkyl, aryl, heterocyclyl, --CN, --OR⁷, --S(O)₂ R¹³, --COR⁷, --CO₂ R⁷, --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --CONR⁶ R⁷, --NR⁸ CO₂ R⁷, or --NR⁶ R⁷,

wherein C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl or C₃ -C₈ cycloalkyl is each substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, --CN, --OR⁷, --S(O)_(n) R¹³, --COR⁷, --CO₂ R⁷, --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R⁷, --NR⁶ R⁷, --CONR⁶ R⁷, aryl and heterocyclyl,

with the proviso that when R³ is aryl, Ar is not imidazolyl;

R⁴ is H, C₁ -C₆ alkyl, C₂ -C₆ alkenyl or C₂ -C₆ alkynyl, wherein C₂ -C₆ alkenyl or C₂ -C₆ alkynyl is optionally substituted with C₁ -C₄ alkyl or C₃ -C₆ cycloalkyl and wherein C₁ -C₆ alkyl is optionally substituted with C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, C₁ -C₄ haloalkyl, --OR⁷, --S(O)_(n) R¹², --CO₂ R⁷, --NR⁶ R⁷ or --NR⁹ COR¹⁰ ;

R⁵ is independently selected at each occurrence from C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, aryl, heterocyclyl, --NO₂, halo, --CN, C₁ -C₄ haloalkyl, --NR⁶ R⁷, --NR⁸ COR⁷, --NR⁸ CO₂ R⁷, --OR⁷, --COR⁷, --CO₂ R⁷, --CONR⁶ R⁷, --CON(OR⁹)R⁷, --SH, and --S(O)_(n) R¹³, wherein C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₃ -C₆ cycloalkyl and C₄ -C₁₂ cycloalkylalkyl are substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, --NO₂, halo, --CN, --OR⁷, --COR⁷, --CO₂ R⁷, --CONR⁶ R⁷, --NR⁶ R⁷, --NR⁸ COR⁷, --NR⁸ CO₂ R⁷ and --S(O)_(n) R¹³ ;

R⁶ and R⁷ are independently selected at each occurrence from H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, aryl, aryl(C₁ -C₄ alkyl)-, heterocyclyl, heterocyclyl(C₁ -C₄ alkyl)-, morpholinoethyl, morpholinopropyl and morpholinobutyl; or --NR⁶ R⁷ taken together as a whole is piperidine, pyrrolidine, piperazine, N-methyl-piperazine, morpholine or thiomorpholine;

wherein C₁ -C₄ alkyl, may be substituted with 0 to 2 substituents independently selected at each occurrence from --OH or C₁ -C₄ alkoxy groups;

R⁸ is independently at each occurrence H or C₁ -C₄ alkyl;

R⁹ and R¹⁰ are independently at each occurrence selected from H, C₁ -C₄ alkyl and C₃ -C₆ cycloalkyl;

R¹¹ is H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, or C₃ -C₆ cycloalkyl;

R¹² is C₁ -C₄ alkyl, C₁ -C₄ haloalkyl or --NR⁶ R⁷ ;

R¹³ is C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, --NR⁶ R⁷, aryl, aryl(C₁ -C₄ alkyl)-, heterocyclyl or heterocyclyl(C₁ -C₄ alkyl)-;

R¹⁴ is C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, --NR¹⁵ R¹⁶ ;

R¹⁵ and R¹⁶ are independently selected at each occurrence from H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl and C₄ -C₁₂ cycloalkylalkyl; or --NR¹⁵ R¹⁶ taken together as a whole is piperidine, pyrrolidine, piperazine, N-methyl-piperazine, morpholine or thiomorpholine;

aryl is phenyl, biphenyl or naphthyl, each substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, --CN, --OR¹⁵, --SH, --S(O)_(n) R¹⁴, --COR¹⁵, --CO₂ R¹⁵, --OC(O)R¹⁴, --NO₂, --NR⁸ COR¹⁵, --N(COR¹⁵)₂, --NR⁸ CONR¹⁵ R¹⁶, --NR⁸ CO₂ R¹⁵, --NR¹⁵ R¹⁶ and --CONR¹⁵ R¹⁶ ;

heterocyclyl is 5- to 10-membered heterocyclic ring which may be saturated, partially unsaturated or aromatic, and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S, wherein the heterocyclic ring is substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, --CN, --OR¹⁵, --SH, --S(O)_(n) R¹⁴, --COR¹⁵, --CO₂ R¹⁵, --OC(O)R¹⁴, --NR⁸ COR¹⁵, --N(COR¹⁵)₂, --NR⁸ CONR¹⁵ R¹⁶, --NR⁸ CO₂ R¹⁵, --NR¹⁵ R¹⁶, and --CONR¹⁵ R¹⁶ ; and

n is independently at each occurrence 0, 1 or 2;

and wherein, when Z is N:

Y is NR⁴, O or S(O)_(n) ;

Ar, R¹, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, aryl, heterocyclyl, heterocyclyl and n are as defined above, but

R³ is C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₃ -C₈ cycloalkyl, C₁ -C₄ haloalkyl, aryl, heterocyclyl, --CN, --S(O)₂ R¹³, --CO₂ R⁷, --COR⁷ or --CONR⁶ R⁷,

wherein C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl or C₃ -C₈ cycloalkyl is each substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, --CN, --OR⁷, --S(O)_(n) R¹³, --COR⁷, --CO₂ R⁷, --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R⁷, --NR⁶ R⁷, --CONR⁶ R⁷, aryl and heterocyclyl,

with the proviso that when R³ is aryl, Ar is not imidazolyl.

[3] Preferred compounds of this invention are compounds of Formula (I) and pharmaceutically acceptable salts and pro-drug forms thereof, wherein:

Z is CR² ;

Y is NR⁴ or O;

Ar is phenyl or pyridyl, each substituted with 0 to 4 R⁵ groups;

R¹ is H, halo, C₁ -C₄ alkyl, cyclopropyl, C₁ -C₄ haloalkyl, --CN, --NR⁶ R⁷, --CONR⁶ R⁷, --OR⁷, --COR⁷, --CO₂ R⁷ or --S(O)_(n) R¹³, wherein C₁ -C₄ alkyl is substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, halo, --CN, --OR⁷, --S(O)_(n) R¹³, --COR⁷, --CO₂ R⁷, --NR⁸ COR⁷, --NR⁸ CO₂ R⁷, --NR⁶ R⁷ and aryl;

R² is H, C₁ -C₄ alkyl, halo, C₁ -C₄ haloalkyl;

R³ is C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₃ -C₈ cycloalkyl, C₁ -C₄ haloalkyl, aryl, heterocyclyl, --CN, --OR⁷, --S(O)₂ R¹³, --COR⁷, --CO₂ R⁷, --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --CONR⁶ R⁷, --NR⁸ CO₂ R⁷, or --NR⁶ R⁷,

wherein C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl or C₃ -C₈ cycloalkyl is each substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, C₁ -C₄ haloalkyl, halo, --CN, --OR⁷, --S(O)_(n) R^(l3), --CO₂ R⁷, --NR⁸ COR⁷, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R⁷, --NR⁶ R⁷, aryl and heterocyclyl;

R⁴ is H, C₁ -C₆ alkyl or C₂ -C₆ alkenyl, wherein C₁ -C₆ alkyl is optionally substituted with C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, --OR⁷, --S(O)_(n) R¹², --CO₂ R⁷, --NR⁶ R⁷ or --NR⁹ COR¹⁰ ;

R⁵ is independently selected at each occurrence from C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₃ -C₆ cycloalkyl, C₄ -C₈ cycloalkylalkyl, aryl, heterocyclyl, C₁ -C₄ haloalkyl, halo, --CN, --NO₂, --NR⁶ R⁷, --COR⁷, --OR⁷, --CONR⁶ R⁷, --CON(OR⁹)R⁷, CO₂ R⁷ and --S(O)_(n) R¹³,

wherein C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₃ -C₆ cycloalkyl and C₄ -C₈ cycloalkylalkyl are substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, --NO₂, halo, --CN, --NR⁶ R⁷, COR⁷, --OR⁷, --CONR⁶ R⁷, CO₂ R⁷ and --S(O)_(n) R¹³ ;

R⁶ and R⁷ are independently selected at each occurrence from H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, aryl, aryl(C₁ -C₄ alkyl)-, heterocyclyl, heterocyclyl(C₁ -C₄ alkyl)-, morpholinoethyl, morpholinopropyl and morpholinobutyl; or --NR⁶ R⁷ taken together as a whole is piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine;

wherein C₁ -C₄ alkyl, may be substituted with 0 to 2 substituents independently selected at each occurrence from --OH or C₁ -C₄ alkoxy groups;

R⁸ is independently at each occurrence H or C₁ -C₄ alkyl;

R⁹ and R¹⁰ are independently at each occurrence selected from H, C₁ -C₄ alkyl and C₃ -C₆ cycloalkyl;

R¹¹ is H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, or C₃ -C₆ cycloalkyl;

R¹² is C₁ -C₄ alkyl, C₁ -C₄ haloalkyl or --NR⁶ R⁷ ;

R¹³ is C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, --NR⁶ R⁷, aryl, aryl(C₁ -C₄ alkyl)-, heterocyclyl or heterocyclyl(C₁ -C₄ alkyl)-;

R¹⁴ is C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, --NR¹⁵ R¹⁶ ;

R¹⁵ and R¹⁶ are independently selected at each occurrence from H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl and C₄ -C₁₂ cycloalkylalkyl; or --NR¹⁵ R¹⁶ taken together as a whole is piperidine, pyrrolidine, piperazine, N-methyl-piperazine, morpholine or thiomorpholine;

aryl is phenyl substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, halo, --CN, --OR¹⁵, --S(O)_(n) R¹⁴, --COR¹⁵, --CO₂ R¹⁵, --NO₂, --NR⁸ COR¹⁵, --NR⁸ CONR¹⁵ R¹⁶, --NR⁸ CO₂ R¹⁵ and --NR¹⁵ R¹⁶ ;

heterocyclyl is pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, imidazolyl, thiazolyl, pyrrolyl, oxazolyl, isoxazolyl or pyrazolyl, each substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, halo, --CN, --OR¹⁵, --S(O)_(n) R¹⁴, --CO₂ R¹⁵, --NO₂, --NR⁸ COR¹⁵, --NR⁸ CONR¹⁵ R¹⁶, --NR⁸ CO₂ R¹⁵, and --NR¹⁵ R¹⁶ ; and

n is independently at each occurrence 0, 1 or 2.

[4] More preferred compounds of this invention are compounds of Formula (I) and pharmaceutically acceptable salts and pro-drug forms thereof, wherein:

Z is CR² ;

Y is NR⁴ ;

Ar is phenyl or pyridyl, each substituted with 0 to 4 R⁵ groups;

R¹ is H, halo, C₁ -C₄ alkyl, cyclopropyl, C₁ -C₃ haloalkyl, --CN, --NR⁶ R⁷, --CONR⁶ R⁷, --COR⁷, --CO₂ R⁷, --OR⁷ or --S(O)_(n) R¹³ wherein C₁ -C₄ alkyl is substituted with 0 to 3 substituents independently selected at each occurrence from C₃ -C₄ cycloalkyl, halo, --CN, --OR⁷, --S(O)_(n) R¹³, --COR⁷, --CO₂ R⁷, --NR⁶ R⁷ ;

R² is H;

R³ is C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₃ -C₆ cycloalkyl, C₁ -C₄ haloalkyl or aryl, wherein C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl or C₃ -C₆ cycloalkyl is each substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, C₁ -C₄ haloalkyl, halo, --CN, --OR⁷, --S(O)_(n) R¹³, --CO₂ R⁷, --NR⁸ COR⁷, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R⁷, --NR⁶ R⁷ and aryl;

R⁴ is H, allyl, or C₁ -C₄ alkyl, wherein C₁ -C₄ alkyl is optionally substituted with C₁ -C₄ alkyl, --OR⁷, --S(O)₂ R¹², --CO₂ R⁷, --NR⁶ R⁷ or --NR⁹ COR¹⁰ ;

R⁵ is independently selected at each occurrence from C₁ -C₆ alkyl, aryl, heterocyclyl, C₁ -C₄ haloalkyl, halo, --CN, --NO₂, --NR⁶ R⁷, --COR⁷, --OR⁷, --CONR⁶ R⁷, --CON(OR⁹)R⁷, --CO₂ R⁷ and --S(O)_(n) R¹³, wherein C₁ -C₆ alkyl is substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, --NO₂, halo, --CN, --NR⁶ R⁷, COR⁷, --OR⁷, --CONR⁶ R⁷, CO₂ R⁷ and --S(O)_(n) R¹³ ;

R⁶ and R⁷ are independently selected at each occurrence from H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl and C₂ -C₈ alkoxyalkyl;

wherein C₁ -C₄ alkyl, may be substituted with 0 to 2 substituents independently selected at each occurrence from --OH or C₁ -C₄ alkoxy groups;

R⁸, R⁹ and R¹⁰ are independently at each occurrence H or C₁ -C₄ alkyl;

R¹² and R¹³ are independently at each occurrence C₁ -C₄ alkyl or --NR⁶ R⁷ ;

R¹⁴ is C₁ -C₄ alkyl or --NR¹⁵ R¹⁶ ;

R¹⁵ and R¹⁶ are independently at each occurrence H, C₁ -C₄ alkyl or C₂ -C₈ alkoxyalkyl;

aryl is phenyl substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, halo, --CN, --OR¹⁵, --S(O)_(n) R¹⁴, --COR¹⁵, --CO₂ R¹⁵, --NO₂ and --NR¹⁵ R¹⁶ ; and

n is independently at each occurrence 0, 1 or 2.

[5] Even more preferred compounds of this invention are compounds of Formula (I) and pharmaceutically acceptable salts and pro-drug forms thereof, wherein:

Z is CR² ;

Y is NR⁴ ;

Ar is phenyl or pyridyl, each substituted with 2 to 4 R⁵ groups;

R¹ is H, Cl, Br, methyl, ethyl, cyclopropyl, or --CN,

R² is H;

R³ is C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₃ -C₆ cycloalkyl, C₁ -C₄ haloalkyl or aryl, wherein C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl or C₃ -C₆ cycloalkyl is each substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, --CF₃, halo, --CN, --OR⁷, and aryl;

R⁴ is H, methyl, ethyl, i-propyl, n-propyl, n-butyl, i-butyl, s-butyl, n-butyl, or allyl;

R⁵ is independently selected at each occurrence from methyl, ethyl, i-propyl, n-propyl, aryl, --CF₃, halo, --CN, --N(CH₃)₂, --C(═O)CH₃, --OCH₃, --OCH₂ CH₃, --OCF₃, and --S(O)₂ CH₃ ;

R¹⁴ is C₁ -C₄ alkyl or --NR¹⁵ R¹⁶ ;

R¹⁵ and R¹⁶ are independently at each occurrence H, C₁ -C₄ alkyl or C₂ -C₈ alkoxyalkyl;

aryl is phenyl substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, halo, --CN, --OR¹⁵, --S(O)_(n) R¹⁴, --COR¹⁵, --CO₂ R¹⁵, --NO₂ and --NR¹⁵ R¹⁶ ; and

n is independently at each occurrence 0, 1 or 2.

[6] Specifically preferred compounds of this invention are compounds of Formula (I), pharmaceutically acceptable salts and pro-drug forms thereof, which are:

3-[(2,4-Dibromophenyl)amino]-5-chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone;

3-[[2-Bromo-4-(1-methylethyl)phenyl]amino]-5-Chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone;

3-[(2,4-Dibromophenyl)ethylamino]-5-Chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone;

3-[[2-Bromo-4-(1-methylethyl)phenyl]ethylamino]-5-chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone;

3-[(2,4,6-Trimethylphenyl)amino]-5-Chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone;

3-[(2,4,6-Trimethylphenyl)ethylamino]-5-Chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone;

(+/-)-3-[(2,4,6-Trimethylphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone;

3-[(2-Bromo-4,6-dimethoxyphenyl)amino]-5-Chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone;

3-[(2-Cyano-4,6-dimethylphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone;

(+/-)-3-[(2-Bromo-4,6-dimethoxyphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone;

(+/-)-3-[(2-Chloro-4,6-dimethoxyphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)propyl]-2 (1H)-pyrazinone;

(+/-)-3-[(4,6-Dimethyl-2-iodophenyl)amino]-5-Chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone;

3-[(2-Cyano-4,6-dimethylphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone;

(+/-)-3-[(2-Bromo-4,6-dimethylphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)propyl]-2 (1H)-pyrazinone;

(+/-)-3-[(4-Bromo-2,6-dimethylphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone;

(+/-)-3-[(4-Acetyl-2,6-dimethylphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone;

(+/-)-3-[(2-Acetyl-4,6-dimethylphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone;

(+/-)-3-[(4,6-Dimethyl-2-thiomethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2 (1H)-pyrazinone;

(+/-)-3-[(4,6-Dimethyl-2-methylsulfonylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone;

(+/-)-3-[(4-Chloro-2-iodo-6-methylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone;

3-[(2,4,6-Trimethylphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone;

3-[(2,4,6-Trimethylphenyl)amino]-5-Chloro-1-phenyl-2(1H)-pyrazinone;

(+/-)-3-[(2,4-Dibromophenyl)amino]-5-methyl-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone;

(+/-)-3-[[2-Bromo-4-(1-methylethyl)phenyl]amino]-5-methyl-1-[1-(methoxymethyl)propyl]-2 (1H)-pyrazinone;

(+/-)-3-[(2,4,6-Trimethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone;

3-[(2,4,6-Trimethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone;

3-[(2,4-Dichloro-6-methylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone;

3-[(2,4-Dichloro-6-methylphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone;

3-[(2,4-Dibromo-6-methylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone;

(+/-)-3-[(2,4,6-Trimethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone;

(+/-)-3-[(2,4,6-Trimethylphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone;

3-[(2,4,6-Trimethylphenyl)amino]-5-Chloro-1-[1-(2-methoxyethyl)-3-methoxypropyl]-2(1H)-pyrazinone;

(+/-)-3-[(2,4-Dimethyl-6-methoxyphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone;

(+/-)-3-[(2,4-Dimethyl-6-methoxyphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone;

(+/-)-3-[(2,4-Dimethyl-6-methoxyphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone;

(+/-)-3-[(4-Bromo-2,6-dimethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone;

(+/-)-3-[(2-Chloro-4,6-dimethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2 (1H)-pyrazinone;

(+/-)-3-[[2,4-Dimethyl-6-(methoxymethyl)phenyl]amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone;

3-[(2,4-Dimethyl-6-methoxyphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone;

3-[(4-Bromo-2,6-dimethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone;

3-[(2-Chloro-4,6-dimethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone;

3-[[2,4-Dimethyl-6-(methoxymethyl)phenyl]amino]-5-methyl-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone;

(+/-)-3-[(2,4-Dimethyl-6-methoxyphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone;

(+/-)-3-[(4-Bromo-2,6-dimethylphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone;

(+/-)-3-[(2-Chloro-4,6-dimethylphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone;

(+/-)-3-[[2,4-Dimethyl-6-(methoxymethyl)phenyl]amino]-5-Chloro-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone;

3-[(2,4-Dimethyl-6-methoxyphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone;

3-[(4-Bromo-2,6-dimethylphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone;

3-[(2-Chloro-4,6-dimethylphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone;

3-[[2,4-Dimethyl-6-(methoxymethyl)phenyl]amino]-5-chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone;

(+/-)3-[(2,4-Dimethyl-6-methoxyphenyl)amino]-5-Chloro-1-(2-methoxy-1-methylethyl)-2(1H)-pyrazinone;

(+/-)3-[(4-Bromo-2,6-dimethylphenyl)amino]-5-Chloro-1-(2-methoxy-1-methylethyl)-2(1H)-pyrazinone;

(+/-)3-[(4-Bromo-2,6-dimethylphenyl)amino]-5-Chloro-1-[1-(ethoxymethyl)propyl]-2(1H)-pyrazinone;

(+/-)3-[(4-Bromo-2,6-dimethylphenyl)amino]-5-Chloro-1-(2-ethoxy-1-methylethyl)-2(1H)-pyrazinone; and

(+/-)3-[(4-Bromo-2,6-difluorophenyl)amino]-5-Chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone;

(+/-)-3-[(2-Bromo-4,6-dimethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone;

(+/-)-3-[(2,4-Dimethyl-6-thiomethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone;

(+/-)-3-[(2,4-Dimethyl-6-methylsulfonylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone;

(+/-)-3-[(2,6-Dimethyl-4-(N,N-dimethylamino)phenyl)-amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone;

(+/-)-3-[(2,4-Dichloro-6-methylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone;

(+/-)-3-[(4-Chloro-2,6-dimethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone;

(+/-)-3-[(2,6-Dimethyl-4-thiomethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone;

(+/-)-3-[(2,6-Dimethyl-4-methoxyphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone;

(+/-)-3-[(2,6-Dimethyl-4-methylsulfonylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone;

(+/-)-3-[(4-Acetyl-2,6-dimethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone;

3-[(4-Bromo-2,6-dimethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone;

3-[(4-Acetyl-2,6-dimethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone;

3-[(2,6-Dimethyl-4-thiomethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone;

3-[(2,6-Dimethyl-4-methylsulfonylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone;

3-[(2,6-Dimethyl-4-(N,N-dimethylamino)phenyl)amino]-5-methyl-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone;

3-[(4,6-Dimethyl-2-(N,N-dimethylamino)phenyl)amino]-5-methyl-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone;

(+/-)3-[(2,6-Dimethyl-4-thiomethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone;

(+/-)3-[(2,6-Dimethyl-4-methylsulfonylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone;

(+/-)3-[(2-Chloro-4,6-dimethylphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone;

(+/-)3-[(4-Bromo-6-methoxy-2-methylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone;

3-[(2,6-Dimethyl-4-thiomethylphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone;

3-[(2,6-Dimethyl-4-methylsulfonylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone;

3-[(4-Bromo-6-methoxy-2-methylphenyl)amino]-5-Chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; and

3-[(2,4,6-Trimethylphenyl)amino]-5-methyl-1-(1-ethylpropyl)-2(1H)-pyrazinone.

[7] A second embodiment of preferred compounds of this invention are compounds of Formula (I) and pharmaceutically acceptable salts and pro-drug forms thereof, wherein:

Z is CR² ;

Y is NR⁴ or O;

Ar is phenyl or pyridyl, each substituted with 0 to 4 R⁵ groups;

R¹ is H, halo, C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₃ -C₈ cycloalkyl, C₁ -C₄ haloalkyl, aryl, heterocyclyl, --CN, --OR⁷, --SH, --S(O)_(n) R¹³, --COR⁷, --CONR⁶ R⁷, --CO₂ R⁷, --OC(O)R¹³, --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R⁷, or --NR⁶ R⁷,

wherein C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl or C₃ -C₈ cycloalkyl is each substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, --CN, --OR⁷, --SH, --S(O)_(n) R¹³, --COR⁷, --CO₂ R⁷, --OC(O)R¹³, --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R⁷, --NR⁶ R⁷, --CONR⁶ R⁷, aryl and heterocyclyl;

R² is H, C₁ -C₄ alkyl, halo, C₁ -C₄ haloalkyl;

R³ is C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, C₁ -C₄ haloalkyl and --NR⁶ R⁷,

wherein C₁ -C₄ alkyl is substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, C₁ -C₄ haloalkyl, halo, --CN, --OR⁷, --S(O)_(n) R¹³, --COR⁷, --CO₂ R⁷, --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R⁷, --NR⁶ R⁷ and --CONR⁶ R⁷ ;

R⁴ is H, C₁ -C₆ alkyl or C₂ -C₆ alkenyl, wherein C₁ -C₆ alkyl is optionally substituted with C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, --OR⁷, --S(O)_(n) R¹², --CO₂ R⁷, --NR⁶ R⁷ or --NR⁹ COR¹⁰ ;

R⁵ is independently selected at each occurrence from C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, aryl, heterocyclyl, --NO₂, halo, --CN, C₁ -C₄ haloalkyl, --NR⁶ R⁷, --NR⁸ COR⁷, --NR⁸ CO₂ R⁷, --OR⁷, --COR⁷, --CO₂ R⁷, --CONR⁶ R⁷, --CON(OR⁹)R⁷ and --S(O)_(n) R¹³, wherein C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₃ -C₆ cycloalkyl and C₄ -C₁₂ cycloalkylalkyl are substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, --NO₂, halo, --CN, --OR⁷, --COR⁷, --CO₂ R⁷, --CONR⁶ R⁷, --NR⁶ R⁷, --NR⁸ COR⁷, --NR⁸ CO₂ R⁷ and --S(O)_(n) R¹³ ;

R⁶ and R⁷ are independently selected at each occurrence from H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, aryl, aryl(C₁ -C₄ alkyl)-, heterocyclyl, heterocyclyl (C₁ -C₄ alkyl)-, morpholinoethyl, morpholinopropyl and morpholinobutyl; or --NR⁶ R⁷ taken together as a whole is piperidine, pyrrolidine, piperazine, N-methyl-piperazine, morpholine or thiomorpholine;

wherein C₁ -C₄ alkyl, may be substituted with 0 to 2 substituents independently selected at each occurrence from --OH or C₁ -C₄ alkoxy groups;

R⁸ is independently at each occurrence H or C₁ -C₄ alkyl;

R⁹ and R¹⁰ are independently at each occurrence selected from H, C₁ -C₄ alkyl and C₃ -C₆ cycloalkyl;

R¹¹ is H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, or C₃ -C₆ cycloalkyl;

R¹² is C₁ -C₄ alkyl, C₁ -C₄ haloalkyl or --NR⁶ R⁷ ;

R¹³ is C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, --NR⁶ R⁷, aryl, aryl(C₁ -C₄ alkyl)-, heterocyclyl or heterocyclyl(C₁ -C₄ alkyl)-;

R¹⁴ is C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, --NR¹⁵ R¹⁶ ;

R¹⁵ and R¹⁶ are independently selected at each occurrence from H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl and C₄ -C₁₂ cycloalkylalkyl; or --NR¹⁵ R¹⁶ taken together as a whole is piperidine, pyrrolidine, piperazine, N-methyl-piperazine, morpholine or thiomorpholine;

aryl is phenyl or naphthyl, each substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, halo, --CN, --OR¹⁵, --S(O)_(n) R¹⁴, --COR¹⁵, --CO₂ R¹⁵, --NO₂, --NR⁸ COR¹⁵, --NR⁸ CONR¹⁵ R¹⁶, --NR⁸ CO₂ R¹⁵ and --NR¹⁵ R¹⁶ ;

heterocyclyl is pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, imidazolyl, thiazolyl, pyrrolyl, oxazolyl, isoxazolyl or pyrazolyl, each substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, halo, --CN, --OR¹⁵, --S(O)_(n) R¹⁴, --CO₂ R¹⁵, --NO₂, --NR⁸ COR¹⁵, --NR⁸ CONR¹⁵ R¹⁶, --NR⁸ CO₂ R¹⁵, and --NR¹⁵ R¹⁶ ; and

n is independently at each occurrence 0, 1 or 2.

[8] More preferred compounds of the second embodiment of this invention are compounds of Formula (I) and pharmaceutically acceptable salts and pro-drug forms thereof, wherein:

Z is CR² ;

Y is NR⁴ ;

Ar is phenyl or pyridyl, each substituted with 0 to 4 R⁵ groups;

R¹ is H, halo, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₃ -C₆ cycloalkyl, C₁ -C₄ haloalkyl, aryl, heterocyclyl, --CN, --OR⁷, --S(O)_(n) R¹³, --COR⁷, --CONR⁶ R⁷, --CO₂ R⁷ or --NR⁶ R⁷,

wherein C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl or C₃ -C₆ cycloalkyl is each substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, --CN, --OR⁷, --SH, --S(O)_(n) R¹³, --COR⁷, --CO₂ R⁷, --OC(O)R¹³, --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R⁷, --NR⁶ R⁷, --CONR⁶ R⁷, aryl and heterocyclyl;

R² is H;

R³ is C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, C₁ -C₄ haloalkyl and --NR⁶ R⁷ ₁,

wherein C₁ -C₄ alkyl is substituted with 0 to 3 substituents independently selected at each occurrence from C₃ -C₆ cycloalkyl, C₁ -C₄ haloalkyl, halo, --CN, --OR⁷, --S(O)_(n) R¹³, --COR⁷, --CO₂ R⁷, --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R⁷, --NR⁶ R⁷ and --CONR⁶ R⁷ ;

R⁴ is H, allyl, or C₁ -C₄ alkyl, wherein C₁ -C₄ alkyl is optionally substituted with C₁ -C₄ alkyl, --OR⁷, --S(O)₂ R¹², --CO₂ R⁷, --NR⁶ R⁷ or --NR⁹ COR¹⁰ ;

R⁵ is independently selected at each occurrence from C₁ -C₆ alkyl, aryl, heterocyclyl, C₁ -C₄ haloalkyl, halo, --CN, --NO₂, --NR⁶ R⁷, --COR⁷, --OR⁷, --CONR⁶ R⁷, --CON(OR⁹)R⁷, --CO₂ R⁷ and --S(O)_(n) R^(l3), wherein C₁ -C₆ alkyl is substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, --NO₂, halo, --CN, --NR⁶ R⁷, COR⁷, --OR⁷, --CONR⁶ R⁷, CO₂ R⁷ and --S(O)_(n) R¹³ ;

R⁶ and R⁷ are independently selected at each occurrence from H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl and C₂ -C₈ alkoxyalkyl;

wherein C₁ -C₄ alkyl, may be substituted with 0 to 2 substituents independently selected at each occurrence from --OH or C₁ -C₄ alkoxy groups;

R⁸, R⁹ and R¹⁰ are independently at each occurrence H or C₁ -C₄ alkyl;

R¹² and R¹³ are independently at each occurrence C₁ -C₄ alkyl or --NR⁶ R⁷ ;

R¹⁴ is C₁ -C₄ alkyl or --NR¹⁵ R¹⁶ ;

R¹⁵ and R¹⁶ are independently at each occurrence H, C₁ -C₄ alkyl or C₂ -C₈ alkoxyalkyl;

aryl is phenyl substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, halo, --CN, --OR¹⁵, --S(O)_(n) R¹⁴, --COR¹⁵, --CO₂ R¹⁵, --NO₂ and --NR¹⁵ R¹⁶ ; and

n is independently at each occurrence 0, 1 or 2.

[10] A third embodiment of preferred compounds of this invention are compounds of Formula (I) and pharmaceutically acceptable salts and pro-drug forms thereof, wherein:

Z is N;

Y is NR⁴ or O;

Ar is phenyl or pyridyl, each substituted with 0 to 4 R⁵ groups;

R¹ is H, halo, C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, aryl, --CN, C₁ -C₄ haloalkyl, --NR⁶ R⁷, --CONR⁶ R⁷, --OR⁷, --COR⁷, --CO₂ R⁷ or --S(O)_(n) R¹³,

wherein C₁ -C₄ alkyl is substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₃ alkyl, C₃ -C₆ cycloalkyl, halo, --CN, --OR⁷, --S(O)_(n) R¹³, --COR⁷, --CO₂ R⁷, --NR⁸ COR⁷, --NR⁸ CO₂ R⁷, --NR⁶ R⁷ and aryl;

R³ is C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₃ -C₈ cycloalkyl, C₁ -C₄ haloalkyl, aryl, heterocyclyl, --CN, --S(O)₂ R¹³, --COR⁷, --CO₂ R⁷ or --CONR⁶ R⁷,

wherein C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl or C₃ -C₈ cycloalkyl is each substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, C₁ -C₄ haloalkyl, halo, --CN, --OR⁷, --S(O)_(n) R^(l3), --CO₂ R⁷, --NR⁸ COR⁷, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R⁷, --NR⁶ R⁷, aryl and heterocyclyl;

R⁴ is H, C₁ -C₆ alkyl or C₂ -C₆ alkenyl, wherein C₁ -C₆ alkyl is optionally substituted with C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, C₁ -C₄ haloalkyl, --OR⁷, --S(O)_(n) R¹², --CO₂ R⁷, --NR⁶ R⁷ or --NR⁹ COR¹⁰ ;

R⁵ is independently selected at each occurrence from C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₃ -C₆ cycloalkyl, C₄ -C₈ cycloalkylalkyl, aryl, heterocyclyl, C₁ -C₄ haloalkyl, halo, --CN, --NO₂, --NR⁶ R⁷, --COR⁷, --OR⁷, --CONR⁶ R⁷, --CON(OR⁹)R⁷, CO₂ R⁷ and --S(O)_(n) R¹³,

wherein C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₃ -C₆ cycloalkyl and C₄ -C₈ cycloalkylalkyl are substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, --NO₂, halo, --CN, --NR⁶ R⁷, COR⁷, --OR⁷, --CONR⁶ R⁷, CO₂ R⁷ and --S(O)_(n) R¹³ ;

R⁶ and R⁷ are independently selected at each occurrence from H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, aryl, aryl(C₁ -C₄ alkyl)-, heterocyclyl, heterocyclyl(C₁ -C₄ alkyl)-, morpholinoethyl, morpholinopropyl and morpholinobutyl; or --NR⁶ R⁷ taken together as a whole is piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine;

wherein C₁ -C₄ alkyl, may be substituted with 0 to 2 substituents independently selected at each occurrence from --OH or C₁ -C₄ alkoxy groups;

R⁸ is independently at each occurrence H or C₁ -C₄ alkyl;

R⁹ and R¹⁰ are independently at each occurrence selected from H, C₁ -C₄ alkyl and C₃ -C₆ cycloalkyl;

R¹¹ is H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, or C₃ -C₆ cycloalkyl;

R¹² is C₁ -C₄ alkyl, C₁ -C₄ haloalkyl or --NR⁶ R⁷ ;

R¹³ is C₁ -C₄ alkyl, C₁ 14 C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, --NR⁶ R⁷, aryl, aryl(C₁ -C₄ alkyl)-, heterocyclyl or heterocyclyl(C₁ -C₄ alkyl)-;

R¹⁴ is C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, --NR¹⁵ R¹⁶ ;

R¹⁵ and R¹⁶ are independently selected at each occurrence from H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl and C₄ -C₁₂ cycloalkylalkyl; or --NR¹⁵ R¹⁶ taken together as a whole is piperidine, pyrrolidine, piperazine, N-methyl-piperazine, morpholine or thiomorpholine;

aryl is phenyl substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, halo, --CN, --OR¹⁵, --S(O)_(n) R¹⁴, --COR¹⁵, --CO₂ R¹⁵, --NO₂, --NR⁸ COR¹⁵, --NR⁸ CONR¹⁵ R¹⁶, --NR⁸ CO₂ R¹⁵ and --NR¹⁵ R¹⁶ ;

heterocyclyl is pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, imidazolyl, thiazolyl, pyrrolyl, oxazolyl, isoxazolyl or pyrazolyl, each substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, halo, --CN, --OR¹⁵, --S(O)_(n) R¹⁴, --CO₂ R¹⁵, --NO₂, --NR⁸ COR¹⁵, --NR⁸ CONR¹⁵ R¹⁶, --NR⁸ CO₂ R¹⁵ and --NR¹⁵ R¹⁶ ; and

n is independently at each occurrence 0, 1 or 2.

[11] More preferred compounds of the third embodiment of this invention are compounds of Formula (I) and pharmaceutically acceptable salts and pro-drug forms thereof, wherein:

Z is N;

Y is NR⁴ ;

Ar is phenyl or pyridyl, each substituted with 0 to 4 R⁵ groups;

R¹ is H, halo, C₁ -C₄ alkyl, C₁ -C₃ haloalkyl, cyclopropyl, --CN, --NR⁶ R⁷, --CONR⁶ R⁷, --COR⁷, --CO₂ R⁷, --OR⁷ or --S(O)_(n) R¹³,

wherein C₁ -C₄ alkyl is substituted with 0 to 3 substituents independently selected at each occurrence from C₃ -C₄ cycloalkyl, halo, --CN, --OR⁷, --S(O)_(n) R¹³, --COR⁷, --CO₂ R⁷, --NR⁶ R⁷ ;

R³ is C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₃ -C₆ cycloalkyl, C₁ -C₄ haloalkyl or aryl,

wherein C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl or C₃ -C₆ cycloalkyl is each substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, C₁ -C₄ haloalkyl, halo, --CN, --OR⁷, --S(O)_(n) R¹³, --CO₂ R⁷, --NR⁸ COR⁷, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R⁷, --NR⁶ R⁷ and aryl;

R⁴ is H, allyl, or C₁ -C₄ alkyl, wherein C₁ -C₄ alkyl is optionally substituted with C₁ -C₄ alkyl, --OR⁷, --S(O)₂ R¹², CO₂ R⁷, --NR⁶ R⁷ or --NR⁹ COR¹⁰ ;

R⁵ is independently selected at each occurrence from C₁ -C₆ alkyl, aryl, heterocyclyl, C₁ -C₄ haloalkyl, halo, --CN, --NO₂, --NR⁶ R⁷, --COR⁷, --OR⁷, --CONR⁶ R⁷, --CON(OR⁹)R⁷, --CO₂ R⁷ and --S(O)_(n) R¹³, wherein C₁ -C₆ alkyl is substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, --NO₂, halo, --CN, --NR⁶ R⁷, COR⁷, --OR⁷, --CONR⁶ R⁷, CO₂ R⁷ and --S(O)_(n) R¹³ ;

R⁶ and R7 are independently selected at each occurrence from H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl and C₂ -C₈ alkoxyalkyl;

wherein C₁ -C₄ alkyl, may be substituted with 0 to 2 substituents independently selected at each occurrence from --OH or C₁ -C₄ alkoxy groups;

R⁸, R⁹ and R¹⁰ are independently at each occurrence H or C₁ -C₄ alkyl;

R¹² and R¹³ are independently at each occurrence C₁ -C₄ alkyl or --NR⁶ R⁷ ;

R¹⁴ is C₁ -C₄ alkyl or --NR¹⁵ R¹⁶ ;

R¹⁵ and R¹⁶ are independently at each occurrence H, C₁ -C₄ alkyl or C₂ -C₈ alkoxyalkyl;

aryl is phenyl substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, halo, --CN, --OR¹⁵, --S(O)_(n) R¹⁴, --COR¹⁵, --CO₂ R¹⁵, --NO₂ and --NR¹⁵ R¹⁶ ; and

n is independently at each occurrence 0, 1 or 2.

[12] Even more preferred compounds of this invention are compounds of Formula (I) and pharmaceutically acceptable salts and pro-drug forms thereof, wherein:

Z is N;

Y is NR⁴ ;

Ar is phenyl or pyridyl, each substituted with 2 to 4 R⁵ groups;

R¹ is H, methyl, ethyl, cyclopropyl, --CF₃, or --N(CH₃)₂ ;

R³ is C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₃ -C₆ cycloalkyl, C₁ -C₄ haloalkyl or aryl, wherein C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl or C₃ -C₆ cycloalkyl is each substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, --CF₃, halo, --CN, --OR⁷, and aryl;

R⁴ is H, methyl, ethyl, i-propyl, n-propyl, n-butyl, i-butyl, s-butyl, n-butyl, or allyl;

R⁵ is independently selected at each occurrence from methyl, ethyl, i-propyl, n-propyl, aryl, --CF₃, halo, --CN, --N(CH₃)₂, --C(═O)CH₃, --OCH₃, --OCH₂ CH₃, --OCF₃, and --S(O)₂ CH₃ ;

R¹⁴ is C₁ -C₄ alkyl or --NR¹⁵ R¹⁶ ;

R¹⁵ and R¹⁶ are independently at each occurrence H, C₁ -C₄ alkyl or C₂ -C₈ alkoxyalkyl;

aryl is phenyl substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, halo, --CN, --OR¹⁵, --S(O)_(n) R¹⁴, --COR¹⁵, --CO₂ R¹⁵, --NO₂ and --NR¹⁵ R¹⁶ ; and

n is independently at each occurrence 0, 1 or 2.

[13] A fourth embodiment of preferred compounds of this invention are compounds of Formula (I) and pharmaceutically acceptable salts and pro-drug forms thereof, wherein:

Z is N;

Y is NR⁴ or O;

Ar is phenyl or pyridyl, each substituted with 0 to 4 R⁵ groups;

R¹ is H, halo, C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₃ -C₈ cycloalkyl, C₁ -C₄ haloalkyl, aryl, heterocyclyl, --CN, --OR⁷, --SH, --S(O)_(n) R¹³, --COR⁷, --CONR⁶ R⁷, --CO₂ R⁷, --OC(O)R¹³, --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R⁷, or --NR⁶ R⁷, wherein C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl or C₃ -C₈ cycloalkyl is each substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, --CN, --OR⁷, --SH, --S(O)_(n) R¹³, --COR⁷, --CO₂ R⁷, --OC(O)R¹³, --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R⁷, --NR⁶ R⁷, --CONR⁶ R⁷, aryl and heterocyclyl;

R³ is C₁ -C₄ alkyl, --CN, C₃ -C₆ cycloalkyl, C₁ -C₄ haloalkyl, --OR⁷, --COR⁷, --CO₂ R⁷ or --CONR⁶ R⁷,

wherein C₁ -C₄ alkyl is substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, C₁ -C₄ haloalkyl, halo, --CN, --OR⁷, --S(O)_(n) R¹³, --COR⁷, --CO₂ R⁷, --NR⁸ COR⁷, --N (COR⁷)₂, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R⁷, --NR⁶ R⁷ and --CONR⁶ R⁷ ;

R⁴ is H, C₁ -C₆ alkyl or C₂ -C₆ alkenyl, wherein C₁ -C₆ alkyl is optionally substituted with C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, C₁ -C₄ haloalkyl, --OR⁷, --S(O)_(n) R¹², --CO₂ R⁷, --NR⁶ R⁷ or --NR⁹ COR¹⁰ ;

R⁵ is independently selected at each occurrence from C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, aryl, heterocyclyl, --NO₂, halo, --CN, C₁ -C₄ haloalkyl, --NR⁶ R⁷, --NR⁸ COR⁷, --NR⁸ CO₂ R⁷, --OR⁷, --COR⁷, --CO₂ R⁷, --CONR⁶ R⁷, --CON(OR⁹)R⁷ and --S(O)_(n) R¹³, wherein C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₃ -C₆ cycloalkyl and C₄ -C₁₂ cycloalkylalkyl are substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, --NO₂, halo, --CN, --OR⁷, --COR⁷, --CO₂ R⁷, --CONR⁶ R⁷, --NR⁶ R⁷, --NR⁸ COR⁷, --NR⁸ CO₂ R⁷ and --S(O)_(n) R¹³ ;

R⁶ and R⁷ are independently selected at each occurrence from H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, aryl, aryl(C₁ -C₄ alkyl)-, heterocyclyl, heterocyclyl(C₁ -C₄ alkyl)-, morpholinoethyl, morpholinopropyl and morpholinobutyl; or NR⁶ R⁷ taken together as a whole is piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine;

wherein C₁ -C₄ alkyl, may be substituted with 0 to 2 substituents independently selected at each occurrence from --OH or C₁ -C₄ alkoxy groups;

R⁸ is independently at each occurrence H or C₁ -C₄ alkyl;

R⁹ and R¹⁰ are independently at each occurrence selected from H, C₁ -C₄ alkyl and C₃ -C₆ cycloalkyl;

R¹¹ is H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, or C₃ -C₆ cycloalkyl;

R¹² is C₁ -C₄ alkyl, C₁ -C₄ haloalkyl or --NR⁶ R⁷ ;

R¹³ is C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, --NR⁶ R⁷, aryl, aryl(C₁ -C₄ alkyl)-, heterocyclyl or heterocyclyl(C₁ -C₄ alkyl)-;

R¹⁴ is C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, --NR¹⁵ R¹⁶ ;

R¹⁵ and R¹⁶ are independently selected at each occurrence from H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl and C₄ -C₁₂ cycloalkylalkyl; or --NR¹⁵ R¹⁶ taken together as a whole is piperidine, pyrrolidine, piperazine, N-methyl-piperazine, morpholine or thiomorpholine;

aryl is phenyl or naphthyl, each substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, halo, --CN, --OR¹⁵, --S(O)_(n) R¹⁴, --COR¹⁵, --CO₂ R¹⁵, --NO₂, --NR⁸ COR¹⁵, --NR⁸ CONR¹⁵ R¹⁶, --NR⁸ CO₂ R¹⁵ and --NR¹⁵ R¹⁶ ;

heterocyclyl is pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, imidazolyl, thiazolyl, pyrrolyl, oxazolyl, isoxazolyl or pyrazolyl, each substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, halo, --CN, --OR¹⁵, --S(O)_(n) R¹⁴, --CO₂ R¹⁵, --NO₂, --NR⁸ COR¹⁵, --NR⁸ CONR¹⁵ R¹⁶, --NR⁸ CO₂ R¹⁵, and --NR¹⁵ R¹⁶ ; and

n is independently at each occurrence 0, 1 or 2.

[14] More preferred compounds of the fourth embodiment of this invention are compounds of Formula (I) and pharmaceutically acceptable salts and pro-drug forms thereof, wherein:

Z is N;

Y is NR⁴ ;

Ar is phenyl or pyridyl, each substituted with 0 to 4 R⁵ groups;

R¹ is H, halo, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₃ -C₆ cycloalkyl, C₁ -C₄ haloalkyl, aryl, heterocyclyl, --CN, --OR⁷, --S(O)_(n) R¹³, --COR⁷, --CONR⁶ R⁷, --CO₂ R⁷ or --NR⁶ R⁷,

wherein C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl or C₃ -C₆ cycloalkyl is each substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, --CN, --OR⁷, --SH, --S(O)_(n) R¹³, --COR⁷, --CO₂ R⁷, --OC(O)R¹³, --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R⁷, --NR⁶ R⁷, --CONR⁶ R⁷, aryl and heterocyclyl;

R³ is C₁ -C₄ alkyl, --CN, C₃ -C₆ cycloalkyl, C₁ -C₄ haloalkyl, --OR⁷, --COR⁷ or --CO₂ R⁷,

wherein C₁ -C₄ alkyl is substituted with 0 to 3 substituents independently selected at each occurrence from C₃ -C₆ cycloalkyl, C₁ -C₄ haloalkyl, halo, --CN, --OR⁷, --S(O)_(n) R¹³, --COR⁷, --CO₂ R⁷, --NR⁸ COR⁷, --NR⁶ R⁷ and --CONR⁶ R⁷ ;

R⁴ is H, allyl, or C₁ -C₄ alkyl, wherein C₁ -C₄ alkyl is optionally substituted with C₁ -C₄ alkyl, --OR⁷, --S(O)₂ R¹², --CO₂ R⁷, --NR⁶ R⁷ or --NR⁹ COR¹⁰ ;

R⁵ is independently selected at each occurrence from C₁ -C₆ alkyl, aryl, heterocyclyl, C₁ -C₄ haloalkyl, halo, --CN, --NO₂, --NR⁶ R⁷, --COR⁷, --OR⁷, --CONR⁶ R⁷, --CON(OR⁹)R⁷, --CO₂ R⁷ and --S(O)_(n) R¹³, wherein C₁ -C₆ alkyl is substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, --NO₂, halo, --CN, --NR⁶ R⁷, COR⁷, --OR⁷, --CONR⁶ R⁷, CO₂ R⁷ and --S(O)_(n) R¹³ ;

R⁶ and R⁷ are independently selected at each occurrence from H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl and C₂ -C₈ alkoxyalkyl;

wherein C₁ -C₄ alkyl, may be substituted with 0 to 2 substituents independently selected at each occurrence from --OH or C₁ -C₄ alkoxy groups;

R⁸, R⁹ and R¹⁰ are independently at each occurrence H or C₁ -C₄ alkyl;

R¹² and R¹³ are independently at each occurrence C₁ -C₄ alkyl or --NR⁶ R⁷ ;

R¹⁴ is C₁ -C₄ alkyl or --NR¹⁵ R¹⁶ ;

R¹⁵ and R¹⁶ are independently at each occurrence H, C₁ -C₄ alkyl or C₂ -C₈ alkoxyalkyl;

aryl is phenyl substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, halo, --CN, --OR¹⁵, --S(O)_(n) R¹⁴, --COR¹⁵, --CO₂ R¹⁵, --NO₂ and --NR¹⁵ R¹⁶ ; and

n is independently at each occurrence 0, 1 or 2.

A fifth embodiment of this invention is the method of treating affective disorders, anxiety, depression, post-traumatic stress disorders, supranuclear palsy, seizure disorders, stroke, irritable bowel syndrome, immune suppression, Alzheimer's disease, gastrointestinal disease, anorexia nervosa or other eating disorders, drug or alcohol withdrawal symptoms, drug addiction, inflammatory disorders, or fertility problems in a mammal in need of such treatment comprising administering to the mammal a therapeutically effective amount of a compound of Formula I.

A sixth embodiment of this invention are pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Formula I.

This invention also includes intermediate compounds useful in preparation of the CRF antagonist compounds and processes for making those intermediates, as described in the following description and claims.

The CRF antagonist compounds provided by this invention (and especially labelled compounds of this invention) are also useful as standards and reagents in determining the ability of a potential pharmaceutical to bind to the CRF receptor.

DETAILED DESCRIPTION OF INVENTION

Many compounds of this invention have one or more asymmetric centers or planes. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are included in the present invention. Many geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds, and all such stable isomers are contemplated in the present invention. The compounds may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. All chiral, (enantiomeric and diastereomeric) and racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.

The term "alkyl" includes both branched and straight-chain alkyl having the specified number of carbon atoms. For example, the term "C₁ -C₁₀ alkyl" denotes alkyl having 1 to 10 carbon atoms; thus, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl, wherein, for example, butyl can be --CH₂ CH₂ CH₂ CH₃, --CH₂ CH(CH₃)₂, --CH(CH₃)CH₂ CH₃ or --CH(CH₃)₃.

The term "alkenyl" includes hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon--Carbon bonds which may occur in any stable point along the chain. For example, the term "C₂ -C₁₀ alkenyl" denotes alkenyl having 2 to 10 carbon atoms; thus, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl and decenyl, such as allyl, propargyl, 1-buten-4-yl, 2-buten-4-yl and the like, wherein, for example, butenyl can be, but is not limited to, --CH═CH₂ CH₂ CH₃, --CH₂ CH═CHCH₃, --CH₂ CH₂ CH═CH₂, --CH═C(CH₃)₂ or --CH═CHCH═CH₂.

The term "alkynyl" includes hydrocarbon chains of either a straight or branched configuration and one or more triple carbon--carbon bonds which may occur in any stable point along the chain. The term "C₂ -C₁₀ alkynyl" denotes alkynyl having 2 to 10 carbon atoms; thus, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl and decynyl.

The term "haloalkyl" is intended to include both branched and straight-chain alkyl having the specified number of carbon atoms, substituted independently with 1 or more halogen, such as, but not limited to, --CH₂ F, --CHF₂, --CF₃, --CF₂ Br, --CH₂ CF₃, --CF₂ CF₃, --CH(CF₃)₂ and the like.

The term "alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge.

The term "cycloalkyl" is intended to include saturated ring groups having the specified number of carbon atoms, including mono-, bi- or poly--Cyclic ring systems, such as cyclopropyl (c-Pr), cyclobutyl (c-Bu), cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, [3.3.0]bicyclooctyl, [2.2.2]bicyclooctyl and so forth.

As used herein, the term "heterocyclyl" or "heterocyclic" is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which may be saturated, partially unsaturated, or aromatic, and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. Examples of such heterocycles include, but are not limited to, pyridyl (pyridinyl), pyrimidinyl, furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, isoxazolinyl, isoxazolyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl or octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolinyl, isoxazolyl, oxazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazole, carbazole, β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenarsazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzothienyl, 2,3-dihydrobenzofuranyl or 2,3-dihydrobenzothienyl.

The term "halo" or "halogen" includes fluoro, chloro, bromo and iodo.

The term "substituted", as used herein, means that one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom are replaced.

Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By "stable compound" or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

The term "pharmaceutically acceptable salts" includes acid or base salts of the compounds of formula (I). Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.

Pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.

"Prodrugs" are considered to be any covalently bonded carriers which release the active parent drug of formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of formula (I) are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds wherein hydroxy, amine, or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I); and the like.

The term "therapeutically effective amount" of a compound of this invention means an amount effective to antagonize abnormal level of CRF or treat the symptoms of affective disorder, anxiety or depression in a host.

Synthesis

The pyrazinones and triazinones of this invention can be prepared by one of the general schemes outlined below (Scheme 1-6).

Compounds of the Formula (I) wherein Z═CH, Y═NR⁴, R¹ =halogen and R² =H can be prepared as shown in Scheme 1. Compounds wherein R² is a substituent other than H as defined in the broad scope of the invention can also be prepared as shown in Scheme 1 by using the corresponding R² COH substituted aldehydes or ClCHR² CN substituted haloacetonitriles. ##STR3##

Reaction of a cyanide salt with formaldehyde and the appropriate substituted amine afforded the corresponding aminoacetonitrile which was purified as the hydrochloride salt of Formula (III). Alternatively the same compounds of Formula (III) can be synthesized by reaction of the amine H₂ NR³ with a haloacetonitrile, such as chloroacetonitrile, in the presence of a base such as a tertiary amine or an inorganic base such as K₂ CO₃ in an organic solvent and isolated as a salt of an inorganic acid by treatment with that acid. Amine salt of Formula (III) was treated with an oxalyl halide, R¹ COCOR¹, such as oxalyl chloride or bromide to afford the dihalo compound Formula (IV), as described in Vekemans, J.; Pollers-Wieers, C.; Hoornaert, G. J. Heterocyclic Chem. 20, 919, (1982). Compound Formula (IV) can be coupled with an aryl amine H₂ NAr thermally, in the presence of a strong base such as NaH, KN(SiMe₃)₂, LiN(SiMe₃)₂ or NaN(SiMe₃)₂ in an aprotic organic solvent, or under acid catalysis to give compounds of Formula (V). Compounds of Formula (V) can be alkylated with an alkyl halide R⁴ X to afford compounds of Formula (I).

Compounds where R¹ =alkyl or substituted alkyl can be prepared according to Scheme 2. ##STR4## Reaction of the intermediate of Formula (IV) in Scheme 1, wherein R¹ =X=halogen in Scheme 2, with an alkyl or aryl thiol, HSR", in the presence of base such as NaH affords the adduct of Formula (VII), which may then be treated with a trialkylaluminum as described in Hirota, K.; Kitade, Y.; Kanbe, Y.; Maki, Y.; J. Org. Chem. 57, 5268, (1992), in the presence of a palladium catalyst, such as Pd(PPh₃)₂ Cl₂, to give compounds of Formula (VIII). Condensation of compounds of Formula (VIII) with an aryl amine H₂ NAr under thermal, base, or acid catalyzed conditions gives compounds of Formula (IX). Alternatively (VIII) may be oxidized to the corresponding sulfones with an oxidant such as KMnO₄ and then condensed with the arylamines of formula H₂ NAr to give (IX). The use of appropriately substituted aluminum alkyls, or simple transformations of those substituted alkyls can give access to compounds of Formula (I), where R¹ is a substituted alkyl; see Ratovelomanana, V.; Linstrumelle, G.; Tet. Letters 52, 6001 (1984) and references cited therein.

Compounds of the Formula (I) wherein Z═CH, Y═O or S(O)_(n) and R¹ =halogen can be prepared as shown in Scheme 3. ##STR5##

Reaction of the dihalo intermediate (IV) from Scheme 1 with a phenoxide or thiophenoxide, formed by treatment of the corresponding phenol or thiophenol with an appropriate base, such as NaH in an aprotic solvent, gives the adduct of Formula (X) or (XI). Adduct (XI) may be further oxidized to the sulfoxide or sulfone of Formula (XII), by treatment with the appropriate oxidant, such as a peroxide, NaIO4 or KMnO4.

Compounds of Formula (I) where R¹ =OR, SR and S(O)_(n) R and Z═CH can be introduced on compounds of Formula (V) by copper or copper salt-catalyzed coupling of the corresponding anions RO⁻ and RS⁻ with the pyrazinone bromide. Keegstra, M. A.; Peters, T. H. A.; Brandsma, L.; Tetrahedron, 48, 3633 (1992) describes the addition of phenoxide anions by this method; alternatively, the same conditions can be used for the addition of thiophenoxide anions. Alternatively the same compounds can be synthesized by Scheme 4. ##STR6##

In Scheme 4, reaction of an aminoacetonitrile salt (III), described in Scheme 1, with an oxalyl halide ester (XIII) gives the corresponding amide (XIV), which in turn can be converted to the corresponding imidate salt (XV). This can be cyclized under treatment with a base, such as K₂ CO₃ or Et₃ N to the pyrazinedione of Formula (XVI). This can be converted to the corresponding halide (XIX), using a halogenating agent such as POX₃, oxalyl halide or SOX₂. Alternatively, (XVI) can be converted to the corresponding mesylate, tosylate or triflate, by treatment with the corresponding mesyl, tosyl, or triflic anhydride. Subsequently, (XIX) can be coupled with an aniline to the corresponding adduct of Formula (XX), under the conditions described in Scheme 1, or (XIX) can be coupled with a phenoxide or thiophenoxide as described in Scheme 3 to yield compounds of Formula (I) wherein Y═O or S(O)_(n).

Compounds of Formula (I) wherein R¹ =substituted N and Z═CH can be introduced on compounds of Formula (XV) by reaction with an amine to form the corresponding amidate (XVII) according to Scheme 5. Subsequently, (XVII) can be cyclized, halogenated, and substituted with the appropriate aniline, phenoxide or thiophenoxide as described in Scheme 4 above.

Compounds of Formula I wherein Z═CH and R¹ ═COR⁷ or CO₂ R⁷ can be synthesized from compounds of Formula (VII) by coupling with the appropriate vinyl aluminum or boron reagent in the presence of a palladium catalyst, such as Pd(PPh₃)₂ Cl₂, and further transformations of the vinyl group, using methods known to one skilled in the art. ##STR7##

The compounds of Formula (I) where Z═CH and R¹ or R³ is a functional group not compatible with the procedures of Schemes 1-5 may be prepared from precursors where the interfering functionality of R¹ or R³ is protected using methods known to one skilled in the art (see T. W. Green and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Wiley, New York, 1991); or from precursors bearing R¹ or R³ groups amenable to later conversion into the desired functionality using standard methods (see J. March, Advanced Organic Chemistry, Wiley, New York, 1992).

Triazinones of Formula (I) wherein Z═N and Y═NR⁴, O or S(O)_(n) can be prepared by the synthetic route shown in Scheme 6.

Condensation of a substituted hydrazine with acetamidines or imidates provides amidrazones of Formula (XXX) (Khrustalev, V. A., Zelenin, K. N. Zhurnal Organicheskoi Khimii, Vol. 15, No. 11, 1979, 2280). Cyclization of (XXX) with oxalyl derivatives such as oxalyl chloride provides diones of Formula (XXXI). Treatment of (XXXI) with chlorodehydrating agents such as thionyl chloride, oxalyl chloride or phosphorous oxychloride provides chlorotriazinones of Formula (XXXII), which may be treated with phenols, thiophenols, anilines and their heterocyclic analogs under basic, acidic or thermal conditions to provide compounds of Formula (I) where Z═N and Y═O, S or NH, respectively. In the preceding instance where Y═NH, alkylation of the nitrogen atom with e.g. alkyl iodides provides the related compounds of Formula (I) where Z═N and Y═NR⁴. In the preceding instance where Y═S, oxidation with e.g. mCPBA provides the compounds of Formula (I) where Z═N and Y═S(O) and S(O)₂. The compounds of Formula (I) where Z═N and R¹ or R³ is a functional group not compatible with the procedures of Scheme 4 may be prepared from precursors such as amidrazones of Formula (XXX) or substituted hydrazines where the ##STR8## interfering functionality of R¹ or R³ is protected using methods known to one skilled in the art (see T. W. Green and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Wiley, New York, 1991); or from precursors bearing R¹ or R³ groups amenable to later conversion into the desired functionality using standard methods (see J. March, Advanced Organic Chemistry, Wiley, New York, 1992).

Triazinones of Formula (I) wherein Z═N and Y═NR⁴, O or S(O)_(n) can also be prepared by the synthetic route shown in Scheme 7 ##STR9##

Reaction of ethyl oxalyl chloride with acylated hydrazines of Formula (XXXIV) provides the ethyl oxalyl acylhydrazine derviatives of Formula (XXXV). Compounds of Formula (XXXIV) may be arrived at via condensation of an appropriate ketone or aldehyde with an acylated hydrazide to give acylated hydrazones which may then be reduced under catalytic hydrogenation conditions or by other reducing agents to give the compounds of Formula (XXXIV). The abovementioned acylated hydrazones may also be produced by acylation of a hydrazone made from hydrazine and an appropriate ketone or aldehyde using methods known to one skilled in the art of organic synthesis. Alternatively, compounds of Formula (XXXIV) may also be produced by acylation of an appropriate hydrazine using methods known to one skilled in the art of organic synthesis.

The ethyl esters of compound (XXXV) may then be converted to the primary amide derivatives of Formula (XXXVI) by treatment with an ammonia source such as ammonium hydroxide. Cyclization of (XXXVI) to produce the diones of Formula (XXXI) may be achieved by treatment with, for example, iodotrimethylsilane (TMSI) or POCl₃, or by heating in the presence of a Lewis acid such as ZnCl₂. The oxo group in the 5 position of the 1,2,4-triazin-5,6-diones of Formula (XXXI) may then be converted to a leaving group using reagents such as trifluoromethanesulfonic anhydride under basic conditions to yield compounds of Formula (XXXVII) which may then be treated with phenols, thiophenols, anilines and their heterocyclic analogs under basic conditions to provide compounds of Formula (I)

Additional 1,2,4-triazinone syntheses are disclosed in the literature (A. R. Katritzky and C. W. Rees, Comprehensive Heterocyclic Chemistry, Pergamon Press, New York, Vol. 3, 1984, p. 385) and can be prepared by one skilled in the art.

Intermediates, for example ArYH, H₂ NAr, HOAr or HSAr, in the synthesis of compounds of Formula (I) in Schemes 1-6 may be prepared using standard methods known to one skilled in the art (see, D. Barton and W. D. Ollis, Comprehensive Organic Chemistry, Pergamon Press, New York, Vol. 1-6, 1979; A. R. Katritzky and C. W. Rees, Comprehensive Heterocyclic Chemistry, Pergamon Press, New York, Vol. 1-8, 1984; B. Trost and I. Fleming, Comprehensive Organic Synthesis, Pergamon Press, New York, Vol. 1-9, 1991; and DuPont Merck PCT application WO95/10506).

All of the aforementioned references are hereby incorporated by reference.

EXAMPLE 1 3-[[2-Bromo-4-(1-methylethyl)phenyl]amino]-5-chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone

Part A

Hydrogen chloride (12M, aq., 3.8 mL), methanol (33 mL), water (30 mL), potassium cyanide (3 g), 1-ethylpropylamine (4 g), and formaldehyde (37% w/v, 3.7 mL) were stirred 18 hours at room temperature. Water (200 mL) was added, and the mixture was extracted with 2×200 mL methylene chloride, which was dried over MgSO4 and concentrated to a light oil (5.57 g). The oil was dissolved in ether and 1N HCl was added. The precipitate was collected on paper and dried to give N-(1-ethylpropyl)-aminoacetonitrile hydrochloride as an off-white solid (6.70 g).

Part B: The product from part A (2 g), chloroform (20 mL), and oxalyl chloride (4.68 g) were heated at reflux for 12 hours. The reaction was concentrated to remove excess oxalyl chloride and solvent, and the crude product was chromatographed on silica gel using ethyl acetate/hexane (1:4) as eluent to afford 3,5-dichloro-1-(1-ethylpropyl)-2(1H)-pyrazinone as a white solid (2.09 g).

Part C

The product from part B (0.68 g) and 2-bromo-4-isopropylaniline (1.24 g) were heated at 140° C. for 5 hours. After cooling, methylene chloride (20 mL)was added, filtered, and concentrated. The crude product was chromatographed on silica gel using ethyl acetate/hexane (1:9) as eluent to afford the title compound. 639 mg. mp 118.5-119.5° C. Elemental analysis: calcd. for C₁₈ H₂₃ N₃ OBrCl: C, 52.38; H, 5.626; N, 10.18; Br, 19.36; Cl, 8.599. Found: C, 52.62; H, 5.43; N, 10.13; Br, 19.53; Cl, 8.97.

EXAMPLE 2 3-[[2-Bromo-4-(1-methylethyl)phenyl]ethylamino]-5-chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone

The product from Example 1 (198 mg), N,N-dimethyl-formamide (5 mL), and sodium hydride (60% in oil, 96 mg) were stirred at room temperature 20 minutes. Iodoethane (112 mg) was added and the reaction was stirred overnight at room temperature and quenched with water (10 mL) and saturated sodium chloride (aq., 10 mL). The mixture was extracted with methylene chloride which was dried and concentrated. The crude product was chromatographed on silica gel using ethyl acetate/hexane (1:19) as eluent to afford the title compound (125 mg). CI-HRMS calcd. for C₂₀ H₂₈ N₃ OClBr (M+H)⁺ : 440.110427. Found: 440.107480.

EXAMPLE 3 3-[(2,4-Dibromophenyl)amino]-5-Chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone

2,4-Dibromoaniline (500 mg), toluene (8 mL), and sodium hydride (60% in oil, 398 mg) were stirred for 10 minutes at room temperature and then 3,5-dichloro-1-(1-ethylpropyl)-2(1H)-pyrazinone (468 mg, Example 1, part B) was added. The reaction was heated at reflux 3 hours, cooled, and quenched with water (50 mL). The mixture was extracted with ethyl acetate (100 mL), which was washed with brine, then dried and concentrated. The crude product was chromatographed on silica gel using ethyl acetate/hexane (1:19) affording 400 mg of material, which was crystallized from ether/hexane to give the title compound (240 mg). Elemental analysis: calcd. for C₁₅ H₁₆ N₃ OClBr₂ : C, 40.07; H, 3.597; N, 9.356; Cl, 7.895; Br, 35.55. Found: C, 40.41; H, 3.49; N, 9.34; Cl, 8.27; Br, 35.71.

EXAMPLE 4 3-[(2,4-Dibromophenyl)ethylamino]-5-chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone

The title compound was prepared in a manner similar to the product of Example 2. Elemental analysis calcd. for C₁₇ H₂₀ N₃ OClBr₂ : C,42.75; H,4.22; N, 8.807. Found: C, 42.82; H, 4.14; N, 8.67.

EXAMPLE 5 3-[(2,4,6-Trimethylphenyl)amino]-5-chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone

The title compound was prepared in a manner similar to the product of Example 3. Elemental analysis calcd. for C₁₈ H₂₄ N₃ OCl: C, 64.76; H, 7.256; N, 12.59. Found: C, 64.69; H, 7.03; N, 12.55.

EXAMPLE 6 3-[(2,4,6-Trimethylphenyl)ethylamino]-5-chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone

The title compound was prepared in a manner similar to the product of Example 2. Elemental analysis calcd. for C₂₀ H₂₈ N₃ OCl: C, 66.37; H, 7.808; N, 11.61. Found: C, 66.50; H, 7.69; N, 11.51.

EXAMPLE 7 (+/-)-3-[(2,4,6-Trimethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone

The title compound was prepared in a manner similar to the product of Example 3. Elemental analysis calcd. for C₁₈ H₂₄ N₃ O₂ Cl: C, 61.80; H, 6.91; N, 12.01; Cl, 10.13. Found: C, 61.69; H, 7.00; N, 11.93; Cl, 9.87.

EXAMPLE 8 3-[(2-Bromo-4,6-dimethoxyphenyl)amino]-5-chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone

The title compound was prepared in a manner similar to the product of Example 3. Elemental analysis calcd. for C₁₇ H₂₁ N₃ O₃ BrCl: C, 47.40; H, 4.91; N, 9.765. Found: C, 47.06; H, 4.61; N, 9.56.

EXAMPLE 9 3-[(2-Cyano-4,6-dimethylphenyl)amino]-5-chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone

Part A

3-[(2-Iodo-4,6-dimethylphenyl)amino]-5-chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone was prepared in a manner similar to Example 3.

Part B

The product from part A (460 mg), N,N-dimethylformamide (8 mL), cuprous cyanide (97 mg), and sodium cyanide were heated at 120° C. for 18 hours and then at 130° C. for 3 hours. After cooling, ethyl acetate (100 mL) was added to the reaction which was then washed with water (50 mL) and brine (50 mL), dried, and concentrated. The crude product was chromatographed on silica gel using ethyl acetate/hexane (1:4) as eluent. The product was then crystallized from methylene chloride/hexane to afford the title compound (235 mg). Elemental analysis calcd. for C₁₈ H₂₁ N₄ OCl: C, 62.69; H, 6.148; N, 16.25; Cl, 10.28. Found: C, 62.29; H, 6.27; N, 15.99; Cl, 10.20.

EXAMPLE 10 (+/-)-3-[(2-Bromo-4,6-dimethoxyphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone

The title compound was prepared in a manner similar to the product of Example 3. Elemental analysis calcd. for C₁₇ H₂₁ N₃ O₄ BrCl: C, 45.71; H, 4.748; N, 9.416. Found: C, 45.86; H, 4.43; N, 9.26.

EXAMPLE 12 (+/-)-3-[(2-Iodo-4,6-dimethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone

Part A

Chloroacetonitrile (3.2 mL), 2-amino-1-methoxybutane (10.32 g), and deuterochloroform (50 mL) were stirred and heated at reflux for 48 h. Methylene chloride (100 mL) and sodium hydroxide (aq., 1N, 100 mL) were added to the reaction, the layers separated, and the organic layer concentrated to an oil (3.4 g). The oil was dissolved in ether (100 mL) and HCl/ether (1N, 100 mL) was added. The precipitate was collected on paper affording N-[(1-methoxymethyl)propyl]aminoacetonitrile hydrochloride (6.86 g).

Part B

The title compound was prepared in a manner similar to the product of Example 3. Elemental analysis calcd. for C₁₇ H₂₁ N₃ O₂ ClI: C, 44.22; H, 4.58; N, 9.10. Found: C, 44.26; H, 4.60; N, 9.83.

EXAMPLE 15 (+/-)-3-[(4-Bromo-2,6-dimethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone

To (+/-)-3,5-dichloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone (300 mg) and 4-bromo-2,6-dimethylaniline (238 mg) in THF (anhydrous, 9.4 mL) at 0° C. was added sodium bis(trimethylsilyl)amide (1.0 M/THF, 2.6 mL). The mixture was stirred at 0° C. for 10 minutes. Ethyl acetate (100 mL) was added and washed with water (25 mL) and brine (25 mL). The organic layer was dried over MgSO₄ and concentrated and the crude product was chromatographed on silica gel using ethyl acetate/hexane (1:4) as eluent. The product was then crystallized from ethyl acetate/hexane to afford the title compound (419 mg). Elemental analysis calcd. for C₁₇ H₂₁ N₃ O₂ BrCl: C, 49.23; H, 5.10; N, 10.13. Found: C, 49.33; H, 5.05; N, 10.09.

EXAMPLE 16 (+/-)-3-[(4-Acetyl-2,6-dimethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone

To the product of Example 15 (250 mg), bis(triphenylphosphine)palladium(II) chloride (11 mg), and tetrakis(triphenylphosphine)palladium(0) (17 mg) in a dry flask under nitrogen was added toluene (1.5 mL) and 1-ethoxyvinyl tributyl tin (260 mg). The reaction was heated at reflux 18 hours, and then concentrated in vacuo. The residue was taken up in ether (15 mL) and saturated aqueous potassium fluoride (15 mL), and filtered. The layers were separated, and the ether layer was stirred with 1N HCl (aq., 15 mL). The layers were separated and the ether layer was dried over MgSO₄ and concentrated. The crude product was chromatographed on silica gel using ethyl acetate/hexane (3:7) as eluent to afford the title compound (90 mg). Elemental analysis calcd. for C₁₉ H₂₄ N₃ O₃ Cl: C, 60.39; H, 6.40; N, 11.12. Found: C, 60.51; H, 6.31; N, 11.00.

EXAMPLE 16a (+/-)-3-[(4-Acetyl-2-methoxy-6-methylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone

The title compound was prepared in a manner similar to the product of Example 16. Elemental analysis calcd. for C₁₉ H₂₄ N₃ O₄ Cl: C, 57.94; H, 6.14; N, 10.67. Found: C, 57.70; H, 5.98; N, 10.41.

EXAMPLE 20 (+/-)-3-[(4-Chloro-2-iodo-6-methylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone

The title compound was prepared in a manner similar to the product of Example 3. Elemental analysis calcd. for C₁₆ H₁₈ N₃ O₂ Cl₂ I: C, 39.86; H, 3.76; N, 8.725. Found: C, 40.00; H, 3.69; N, 8.64.

EXAMPLE 21 3-[(2,4,6-Trimethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone

Part A

To serinol (9.90 g) in DMF (200 mL) was added triethyl amine (14.6 mL) and then chlorotriphenylmethane (24.3 g). The reaction mixture was stirred at room temperature for 18 hours. Toluene (800 mL) was added and washed with water (500 mL and 250 mL) and brine (250 mL), and then dried over K₂ CO₃ and concentrated to dryness. The product was crytallized from benzene/hexane (1:1) to afford product (14.57 g).

Part B

The product from part A (14.57 g), sodium hydroxide (17.5 g), and iodomethane (8.8 mL) were stirred overnight in DMSO (220 mL) at room temperature. Water (500 mL) was added and extracted with ethyl acetate (3×250 mL). The extracts were washed with water (2×250 mL) and brine (200 mL), dried over K₂ CO₃, and concentrated to give product (14.46 g).

Part C

The product from part B (14.46 g) and hydrogen chloride (1M/Et₂ O, 84 mL) were stirred in methanol (300 mL) at room temperature for 6 hours. The solution was washed with hexane (3×300 mL), concentrated, and co-evaporated with ethanol affording 2-amino-1,3-methoxypropane (5.69 g).

Part D

The title compound was prepared in a manner similar the product of Example 3. Elemental analysis calcd. for C₁₈ H₂₄ N₃ O₃ Cl: C, 59.09; H, 6.61; N, 11.49. Found: C, 20 59.27; H, 6.53; N, 11.47.

EXAMPLE 30a (+/-)-3-[(2-Chloro-4,6-dimethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone

The title compound was prepared in a manner similar to the product of Example 84. Elemental analysis calcd. for C18H24N3O2Cl: C, 61.80; H, 6.91; N, 12.01. Found: C, 61.70; H, 6.94; N, 11.56.

EXAMPLE 36 3-[(2,4,6-Trimethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone

The title compound was prepared in a manner similar to the product of Example 15. Elemental analysis calcd. for C₁₉ H₂₆ N₃ O₃ Cl: C, 60.07; H, 6.908; N, 11.06. Found: C, 60.22; H, 7.16; N, 10.92.

EXAMPLE 36a 3-[(4-Bromo-2-methoxy-6-methylphenyl)amino]-5-chloro-l-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone

The title compound was prepared in a manner similar to the product of Example 15. Elemental analysis calcd. for C₁₈ H₂₃ N₃ O₄ ClBr: C, 46.92; H, 5.03; N, 9.129. Found: C, 47.29; H, 5.03; N, 8.98.

EXAMPLE 45a 3-[(2-Bromo-6-flouro-4-methylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone

The title compound was prepared in a manner similar to the product of Example 15. Elemental analysis calcd. for C₁₆ H₁₈ N₃ O₃ FClBr: C, 44.21; H, 4.17; N, 9.67. Found: C, 44.35; H, 4.25; N, 9.41.

EXAMPLE 46a 3-[(2-Chloro-4-methoxy-6-methylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone

The title compound was prepared in a manner similar to the product of Example 15. Elemental analysis calcd. for C₁₇ H₂₀ N₃ O₄ C_(12:) C, 50.89; H, 5.02; N, 10.47. Found: C, 50.72; H, 5.33; N, 10.37.

EXAMPLE 49 3-[(4-Bromo-2,6-dimethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone

The title compound was prepared in a manner similar to the product of Example 15. Elemental analysis calcd. for C₁₈ H₂₃ N₃ O₃ ClBr: C, 48.61; H, 5.21; N, 9.457. Found: C, 48.59; H, 5.32; N, 9.45.

EXAMPLE 53 3-[(4-Bromo-2,6-dimethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone

The title compound was prepared in a manner similar to the product of Example 15. Elemental analysis calcd. for C₁₇ H₂₁ N₃ O₃ ClBr: C, 47.40; H, 4.91; N, 9.765. Found: C, 47.52; H, 4.99; N, 9.72.

EXAMPLE 54 3-[(2-Chloro-4,6-dimethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone

The title compound was prepared in a manner similar to the product of Example 15. Elemental analysis calcd. for C₁₇ H₂₁ N₃ O₃ Cl₂ : C, 52.86; H, 5.489; N, 10.88. Found: C, 52.89; H, 5.44; N, 10.72.

EXAMPLE 77 (+/-)-3-[(2,6-Dimethyl-4-thiomethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone

The title compound was prepared in a manner similar to the product of Example 15. Elemental analysis calcd. for C₁₈ H₂₄ N₃ O₂ ClS: C, 56.62; H, 6.33; N, 11.00; S, 8.405. Found: C, 56.66; H, 6.19; N, 10.89; S, 8.45.

EXAMPLE 79 (+/-)-3-[(2-Chloro-4,6-dimethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone

The title compound was prepared in a manner similar to the product of Example 15. Elemental analysis calcd. for C₁₇ H₂₁ N₃ O₂ Cl₂ : C, 55.14; H, 5.726; N, 11.35. Found: C, 55.27; H, 5.70; N, 11.25.

EXAMPLE 80 (+/-)-3-[(4-Bromo-6-methoxy-2-methylphenyl)amino]-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone

The title compound was prepared in a manner similar to the product of Example 15. Elemental analysis calcd. for C₁₇ H₂₁ N₃ O₃ BrCl: C, 47.40; H, 4.91; N, 9.765. Found: C, 47.91; H, 4.95; N, 9.74.

EXAMPLE 81 3-[(2,6-Dimethyl-4-thiomethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone

The title compound was prepared in a manner similar to the product of Example 15. Elemental analysis calcd. for C₁₈ H₂₄ N₃ O₃ ClS: C, 54.33; H, 6.08; N, 10.56; S, 8.06. Found: C, 54.48; H, 6.01; N, 10.46; S, 7.86.

EXAMPLE 83 3-[(4-Bromo-2-methoxy-6-methylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone

The title compound was prepared in a manner similar to the product of Example 15. Elemental analysis calcd. for C₁₇ H₂₁ N₃ O₄ ClBr: C, 45.71; H, 4.748; N, 9.416. Found: C, 45.80; H, 4.70; N, 9.39.

EXAMPLE 84 3-[(2,4,6-Trimethylphenyl)amino]-1-(1-ethylpropyl)-5-methyl-2(1H)-pyrazinone

Part A

N-(1-ethylpropyl)aminoacetonitrile hydrochloride (1.41 g) and oxalyl bromide (2.0 M/CH₂ Cl₂, 13 mL) were heated at reflux for 18 hours. The reaction was concentrated to remove excess oxalyl bromide and solvent, and the crude product was chromatographed on silica gel using ethyl acetate/hexane (1:4) as eluent to afford 3,5-dibromo-1-(1-ethylpropyl)-2(1H)-pyrazinone as a white solid (1.19 g).

Part B

The product from part A (133 mg) and sodium thiomethoxide (29 mg) were combined in THF (1.5 mL) and stirred at 25° C. 4 hours. More sodium thiomethoxide (29 mg) was added and the reaction was stirred for 2 hours more at room temperature. Water (20 mL) was added and extracted with CH₂ Cl₂ (2×20 mL). The organic layers were combined, dried over MgSO₄, and concentrated. The crude product was chromatographed on silica gel using ethyl acetate/hexanes (1:4) as eluent to afford 5-bromo-1-(l-ethylpropyl)-3-thiomethyl-2(1H)-pyrazinone (78 mg).

Part C

The product from part B (200 mg) and Pd(PPh₃)₂ Cl₂ (40 mg) were combined in dry THF (6 mL) under inert atmosphere (N₂). To that a 2M solution AlMe₃ in hexanes (0.5 mL) was added and the reaction was heated at reflux for one hour. The excess AlMe₃ was quenched with water at 0° C. and the mixture was partitioned between ethyl acetate (50 mL) and water (30 mL). The water was separated and extracted with ethyl acetate (50 mL), and the combined EtOAc extracts were washed with brine, dried (MgSO₄) and stripped in vacuo. The crude product was chromatographed on silica gel using ethyl acetate/hexanes as eluent (1:9) to give 1-(1-ethylpropyl)-5-methyl-3-thiomethyl-2(1H)-pyrazinone (100 mg).

Part D

The product from part B (50 mg) and 2,4,6-trimethylaniline (40 mg) were combined in dry THF (2 mL) under inert atmosphere (N₂), and cooled to 0° C. To that a 1M solution NaN(SiMe₃)₂ in THF (0.5 mL) was added dropwise and the reaction was stirred at 0° C. for 20 min. Then an additional NaN(SiMe₃)₂ in THF (0.3 mL) was added and the reaction was stirred at 0° C. for 30 min and at 25° C. for one hour. Then it was quenched with water (30 mL) and extracted with ethyl acetate (80 mL). The ethyl acetate was washed with brine, dried (MgSO₄) and stripped in vacuo. The crude product was chromatographed on silica gel using ethyl acetate/hexanes as eluent (1:9) to give 3-[(2,4,6-trimethylphenyl)amino]-1-(1-ethylpropyl)-5-methyl-2(1H)-pyrazinone (40 mg). mp. 109° C.

EXAMPLE 84a 3-[(2-Chloro-4,6-dimethylphenyl)amino]-1-(1-ethylpropyl)-5-methyl-2(1H)-pyrazinone

The title compound was prepared in a manner similar to the product of Example 84. Elemental analysis calcd. for C₁₈ H₂₄ N₃ OCl: C, 64.76; H, 7.256; N, 12.59. Found: C, 65.12; H, 7.28; N, 12.33.

EXAMPLE 84b 3-[(2-Chloro-4-methoxy-6-methylphenyl)amino]-1-(1-ethylpropyl)-5-methyl-2(1H)-pyrazinone

The title compound was prepared in a manner similar to the product of Example 84. Elemental analysis calcd. for C₁₈ H₂₄ N₃ O₂ Cl: C, 61.80; H, 6.91; N, 12.01. Found: C, 61.72; H, 6.96; N, 11.83.

EXAMPLE 84c 3-[(2,4,6-Trimethylphenyl)amino]-1-(1-ethylpropyl)-5-ethyl-2(1H)-pyrazinone

Part A

5-bromo-1-(1-ethylpropyl)-3-thiomethyl-2(1H)-pyrazinone was prepared in a manner similar to Example 84, parts A and B.

Part B

To the product of part A (2.14 g) and bis(triphenylphosphine)palladium(II) chloride (258 mg) in anhydrous THF (60 mL) under inert atmosphere was added triethyl aluminum (1 M/THF, 14.7 mL). The reaction was heated at reflux 3 hours and then cooled and quenched with water. Ethyl Acetate (200 mL) was added and washed with water and saturated aqueous sodium chloride. The ethyl acetate was dried over MgSO₄ and concentrated in vacuo. The crude product was chromatographed on silica gel using ethyl acetate/hexane (3:17) as eluent to afford 5-ethyl-1-(1-ethylpropyl)-3-thiomethyl-2(1H)-pyrazinone (809 mg).

Part C

The title compound was prepared in a manner similar to the product of Example 84 using the procuct from part B. Elemental analysis calcd. for C₂₀ H₂₉ N₃ O: C, 73.36; H, 8.936; N, 12.83. Found: C, 73.01; H, 8.55; N, 12.69.

EXAMPLE 84d 3-[(2-Chloro-4,6-dimethylphenyl)amino]-1-(1-ethylpropyl)-5-ethyl-2(1H)-pyrazinone

The title compound was prepared in a manner similar to the product of Example 84c. Elemental analysis calcd. for C₁₉ H₂₆ N₃ OCl: C, 65.60; H, 7.53; N, 12.08. Found: C, 65.53; H, 7.33; N, 11.92.

EXAMPLE 85 3-[(2,4,6-Trimethylphenyl)amino]-5-bromo-1-(1-ethylpropyl)-2(1H)-pyrazinone

Part A

N-(1-ethylpropyl)-aminoacetonitrile hydrochloride (1.41 g) and oxalyl bromide (2.0 M, CH₂ Cl2, 13 mL) were heated at reflux for 18 hours. The reaction was concentrated to remove excess oxalyl bromide and solvent, and the crude product was chromatographed on silica gel using ethyl acetate/hexane (1:4) as eluent to afford 3,5-dibromo-1-(1-ethylpropyl)-2(1H)-pyrazinone as a white solid (1.19 g).

Part B

Using the product of part A, the title compound was prepared in a manner similar to the product of Example 3. MS m/z 378, (m+H)⁺, 100%.

EXAMPLE 204 5-[(2,4,6-Trimethylphenyl)amino]-3-methyl-1-(1-ethylpropyl)-1,2,4-triazine-6(1H)-one

Part A

3-Pentanone (18.56 g, 0.215 mol), acetic hydrazide (14.8 g, 0.2 mol), and 200 mL of absolute ethanol were placed in a 500 mL flask. The reaction mixture was reluxed for 18 hr and then evaporated to dryness to afford the desired hydrazone of suitable purity.

The hydrazone was then dissolved in 200 mL of glacial acetic acid containing 1.0 g of PtO₂ and hydrogenated at 50 psi hydrogen pressure for 14 hr. The mixture was decanted from the catalyst and evaporated to dryness to afford 23.9 g of a colorless oil (83% yield for the two steps).

Part B

The 1-acetyl-2-(1-ethylpropyl)hydrazine product from Part A (23.9 g, 0.166 mol) was dissolved in CH₂ Cl₂ (200 mL) and to the stirring solution was added triethylamine (27.9 mL, 0.2 mol) and ethyl oxalyl chloride (19 mL, 0.17 mol). After stirring at room temperature for 3 hr, the reaction mixture was poured into water and the organic layer was separated, dried (Na₂ SO₄), filtered and evaporated in vacuo. To the resultant oil was added ammonium hydroxide (250 mL), THF (100 mL), and ethanol (50 mL). The flask containing the mixture was sealed with a rubber septum and stirred for 18 hr at room temperature. The mixture was then concentrated in vacuo until the reduced volume of solvent remaining was approximately 100 mL, and a white precipitate had formed. The flask was then placed in the refrigerator for 1 hr. The precipitate was collected by vacuum filtration and washed with small volumes of cold water. 26.3 g of a white solid was collected (73% yield). ¹ H NMR (300 MHz, CDCl₃): δ7.78 (s, 1H); 6.74 (br s, 1H); 5.6 (br s, 1H); 4.25 (m, 1H); 2.04 (s, 1H); 1.5 (m, 4H); 0.95 (t, 6H, J=7.3 Hz).

Part C

The 1-oxamyl-1-(3-pentyl)-2-acetylhydrazine product from Part B (2 g, 9.3 mmol) was suspended in chloroform (50 mL) and 2 mL of iodotrimethylsilane was added dropwise. The mixture was allowed to stir at room temperature for 12 hr. The reaction mixture was then partitioned between CH₂ Cl₂ and 1N NaOH. The aqueous layer was separated and made acidic by addition of conc. HCl and then extracted with CH₂ Cl₂. This organic layer was dried (Na₂ SO₄), filtered and evaporated in vacuo to yield 1.2 g of an off-white solid of suitable purity (65% yield). ¹ H NMR (300 MHz, CDCl₃): δ7.85 (br s, 1H); 4.61 (m, 1H); 2.35 (s, 3H); 1.73 (m, 4H); 0.83 (t, 6H, J=7.3 Hz).

Part D

To a solution of the triazine dione product from above (198 mg, 1 mmol) in CH₂ Cl₂ (5 mL) was added trifluoromethanesulfonic anhydride (0.19 mL, 1.1 mmol) and 2,4,6-collidine (0.15 mL, 1.1 mmol). The resulting reaction mixture was stirred at room temperature for 30 min., then 2,4,6-trimethylaniline (162 mg, 1.2 mmol) in 5 mL of THF was added followed by addition of 2,4,6-collidine (0.15 mL, 1.1 mmol). The resulting reaction mixture was stirred at room temperature for 1 hr, at which time TLC showed complete reaction. The reaction mixture was partitioned between water and CH₂ Cl₂. The organic layer was dried (Na₂ SO₄), filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel using EtOAc/hexane (1:9) to afford 260 mg of the title compound (83% yield). mp=133-135° C. ¹ H NMR (300 MHz, CDCl₃): δ7.89 (br s, 1H); 6.94 (s, 2H); 4.72 (m, 1H); 2.31 (s, 3H); 2.19 (s, 9H); 1.9-1.7 (m, 4H); 0.85 (t, 6H, J=7.32 Hz). Mass Spec. (NH₃ --CI): Calc. (M+H)+=315, Obs. (M+H)+=315.

EXAMPLE 703 (+/-)-5-Chloro-1-[1-(methoxymethyl)propyl]-3-(2,4,6-trimethylphenoxy)-2(1H)-pyrazinone

Part A

(+/-)-3,5-dichloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone was prepared in a manner similar to Example 12, part A, and Example 1, part B.

Part B

2,4,6-Trimethylphenol (59 mg) and potassium t-butoxide (48 mg) were added to pyridine (2 mL) at 0° C. The mixture was warmed to ambient temperature and (+/-)-3,5-dichloro-1-[1-(methoxymethyl)propyl]-2(lH)-pyrazinone (98 mg) and copper (I) iodide (19 mg) were added. The reaction mixture was stirred at ambient temperature for three hours and then heated at reflux for three hours and then cooled to 0° C. Ethyl acetate (50 mL) and saturated ammonium chloride (50 mL) were added and the mixture was stirred overnight at ambient temperature. The layers were separated, and the organic layer was washed with 1M ammonium hydroxide (2×50 mL), 1N sodium hydroxide (2×50 mL), 1N hydrochloric acid (2×50 mL), and saturated sodium chloride (50 mL). The ethyl acetate was dried over MgSO₄ and concentrated in vacuo. The crude product was chromatographed on silica gel using ethyl acetate/hexane (1:4) as eluent to afford the title compound (66 mg). mp=116° C. Elemental analysis calcd. for C₁₈ H₂₃ N₂ O₃ Cl: C, 61.62; H, 6.618; N, 7.98. Found: C, 61.45; H, 6.44; N, 7.77.

Various analogs synthesized using Schemes 1, 2 and 3 are listed in Table 1.

                                      TABLE 1                                      __________________________________________________________________________      ##STR10##                                                                     Ex                                                                             No R.sup.1 R.sup.3    Y  Ar             mp/° C.                         __________________________________________________________________________     1  Cl      Et.sub.2 CH                                                                               NH 2-Br-4-iPr-phenyl                                                                             118.5                                  2  Cl      Et.sub.2 CH                                                                               NEt                                                                               2-Br-4-iPr-phenyl                                                                             MS = 440                               3  Cl      Et.sub.2 CH                                                                               NH 2,4-Br.sub.2 -phenyl                                                                          155.5                                  4  Cl      Et.sub.2 CH                                                                               NEt                                                                               2,4-Br.sub.2 -phenyl                                                                          88.1                                   5  Cl      Et.sub.2 CH                                                                               NH 2,4,6-Me.sub.3 -phenyl                                                                        180.8                                  6  Cl      Et.sub.2 CH                                                                               NEt                                                                               2,4,6-Me.sub.3 -phenyl                                                                        93.8                                   7  Cl      MeOCH.sub.2 (Et)CH                                                                        NH 2,4,6-Me.sub.3 -phenyl                                                                        153.8                                  8  Cl      Et.sub.2 CH                                                                               NH 2-Br-4,6-(MeO).sub.2 -phenyl                                                                  181.3                                  9  Cl      Et.sub.2 CH                                                                               NH 2-CN-4,6-Me.sub.2 -phenyl                                                                     174.0                                  10 Cl      MeOCH.sub.2 (Et)CH                                                                        NH 2-Br-4,6-(MeO).sub.2 -phenyl                                                                  175.8                                  11 Cl      MeOCH.sub.2 (Et)CH                                                                        NH 2-Cl-4,6-(MeO).sub.2 -phenyl                          12 Cl      MeOCH.sub.2 (Et)CH                                                                        NH 2-I-4,6-Me.sub.2 -phenyl                                                                      109.4                                  13 Cl      MeOCH.sub.2 (Et)CH                                                                        NH 2-CN-4,6-Me.sub.2 -phenyl                             14 Cl      MeOCH.sub.2 (Et)CH                                                                        NH 2-Br-4,6-Me.sub.2 -phenyl                             15 Cl      MeOCH.sub.2 (Et)CH                                                                        NH 4-Br-2,6-Me.sub.2 -phenyl                                                                     152.8                                  16 Cl      MeOCH.sub.2 (Et)CH                                                                        NH 4-MeCO-2,6-Me.sub.2 -phenyl                                                                   127.1                                  16a                                                                               Cl      MeOCH.sub.2 (Et)CH                                                                        NH 4-MeCO-2-OMe-6-Me-phenyl                                                                      179.8                                  17 Cl      MeOCH.sub.2 (Et)CH                                                                        NH 2-MeCO-4,6-Me.sub.2 -phenyl                           18 Cl      MeOCH.sub.2 (Et)CH                                                                        NH 4,6-Me.sub.2 -2-SMe-phenyl                            19 Cl      MeOCH.sub.2 (Et)CH                                                                        NH 4,6-Me.sub.2 -2-SO.sub.2 Me-phenyl                    20 Cl      MeOCH.sub.2 (Et)CH                                                                        NH 4-Cl-2-I-6-Me-phenyl                                                                          121.8                                  21 Cl      (MeOCH.sub.2).sub.2 CH                                                                    NH 2,4,6-Me.sub.3 -phenyl                                                                        127.2                                  22 Cl      phenyl     NH 2,4,6-Me.sub.3 -phenyl                                23 CN      MeOCH.sub.2 (Et)CH                                                                        NH 2,4,6-Me.sub.3 -phenyl                                24 CONH.sub.2                                                                             MeOCH.sub.2 (Et)CH                                                                        NH 2,4,6-Me.sub.3 -phenyl                                25 COOH    MeOCH.sub.2 (Et)CH                                                                        NH 2,4,6-Me.sub.3 -phenyl                                26 CHO     MeOCH.sub.2 (Et)CH                                                                        NH 2,4,6-Me.sub.3 -phenyl                                27 CH.sub.2 OH                                                                            MeOCH.sub.2 (Et)CH                                                                        NH 2,4,6-Me.sub.3 -phenyl                                28 CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 2,4-Br.sub.2 -phenyl                                  29 CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 2-Br-4-iPr-phenyl                                     30 CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 2,4,6-Me.sub.3 -phenyl                                30a                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 2-Cl-4,6-Me.sub.2 -phenyl                                                                     117.9                                  31 CH.sub.3                                                                               (MeOCH.sub.2).sub.2 CH                                                                    NH 2,4,6-Me.sub.3 -phenyl                                32 CH.sub.3                                                                               (MeOCH.sub.2).sub.2 CH                                                                    NH 2,4-Cl.sub.2 -6-Me-phenyl                             33 Cl      (MeOCH.sub.2).sub.2 CH                                                                    NH 2,4-Cl.sub.2 -6-Me-phenyl                             34 Cl      (MeOCH.sub.2).sub.2 CH                                                                    NH 2,4-Br.sub.2 -6-Me-phenyl                             35 CH.sub.3                                                                               MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        NH 2,4,6-Me.sub.3 -phenyl                                36 Cl      MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        NH 2,4,6-Me.sub.3 -phenyl                                                                        120.0                                  36a                                                                               Cl      MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        NH 4-Br-2-OMe-6-Me-phenyl                                                                        130.9                                  37 Cl      (MeOC.sub.2 H.sub.4).sub.2 CH                                                             NH 2,4,6-Me.sub.3 -phenyl                                38 Cl      MeOCH.sub.2 (Et)CH                                                                        NH 2,4-Me.sub.2 -6-MeO-phenyl                            39 Cl      MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        NH 2,4-Me.sub.2 -6-MeO-phenyl                            40 CH.sub.3                                                                               MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        NH 2,4-Me.sub.2 -6-MeO-phenyl                            41 CH.sub.3                                                                               MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        NH 4-Br-2,6-Me.sub.2 -phenyl                             42 CH.sub.3                                                                               MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        NH 2-Cl-4,6-Me.sub.2 -phenyl                             43 CH.sub.3                                                                               MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        NH 2,4-Me.sub.2 -6-MeOCH.sub.2 -phenyl                   44 CH.sub.3                                                                               (MeOCH.sub.2).sub.2 CH                                                                    NH 2,4-Me.sub.2 -6-MeO-phenyl                            45 CH.sub.3                                                                               (MeOCH.sub.2).sub.2 CH                                                                    NH 4-Br-2,6-Me.sub.2 -phenyl                             45a                                                                               CH.sub.3                                                                               (MeOCH.sub.2).sub.2 CH                                                                    NH 2-Br-6-F-4-Me-phenyl                                                                          138.9                                  46 CH.sub.3                                                                               (MeOCH.sub.2).sub.2 CH                                                                    NH 2-Cl-4,6-Me.sub.2 -phenyl                             46a                                                                               CH.sub.3                                                                               (MeOCH.sub.2).sub.2 CH                                                                    NH 2-Cl-4-OMe-6-Me-phenyl                                                                        128.3                                  47 CH.sub.3                                                                               (MeOCH.sub.2).sub.2 CH                                                                    NH 2,4-Me.sub.2 -6-MeOCH.sub.2 -phenyl                   48 Cl      MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        NH 2,4-Me.sub.2 -6-MeO-phenyl                            49 Cl      MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        NH 4-Br-2,6-Me.sub.2 -phenyl                                                                     138.6                                  50 Cl      MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        NH 2-Cl-4,6-Me.sub.2 -phenyl                             51 Cl      MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        NH 2,4-Me.sub.2 -6-MeOCH.sub.2 -phenyl                   52 Cl      (MeOCH.sub.2).sub.2 CH                                                                    NH 2,4-Me.sub.2 -6-MeO-phenyl                            53 Cl      (MeOCH.sub.2).sub.2 CH                                                                    NH 4-Br-2,6-Me.sub.2 -phenyl                                                                     152.1                                  54 Cl      (MeOCH.sub.2).sub.2 CH                                                                    NH 2-Cl-4,6-Me.sub.2 -phenyl                                                                     132.8                                  55 Cl      (MeOCH.sub.2).sub.2 CH                                                                    NH 2,4-Me.sub.2 -6-MeOCH.sub.2 -phenyl                   56 Cl      MeOCH.sub.2 (Me)CH                                                                        NH 2,4-Me.sub.2 -6-MeO-phenyl                            57 Cl      MeOCH.sub.2 (Me)CH                                                                        NH 4-Br-2,6-Me.sub.2 -phenyl                             58 Cl      EtOCH.sub.2 (Et)CH                                                                        NH 4-Br-2,6-Me.sub.2 -phenyl                             59 Cl      EtOCH.sub.2 (Me)CH                                                                        NH 4-Br-2,6-Me.sub.2 -phenyl                             60 Cl      MeOCH.sub.2 (Et)CH                                                                        NH 4-Br-2,6-F.sub.2 -phenyl                              61 CH.sub.3                                                                               MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        NH 2-Br-4,6-Me.sub.2 -phenyl                             62 CH.sub.3                                                                               MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        NH 2,4-Me.sub.2 -6-SMe-phenyl                            63 CH.sub.3                                                                               MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        NH 2,4-Me.sub.2 -6-SO.sub.2 Me-phenyl                    64 CH.sub.3                                                                               MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        NH 4-NMe.sub.2 -2,6-Me.sub.2 -phenyl                     65 CH.sub.3                                                                               MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        NH 2,4-Cl.sub.2 -6-Me-phenyl                             66 CH.sub.3                                                                               MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        NH 4-Cl-2,6-Me.sub.2 -phenyl                             67 CH.sub.3                                                                               MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        NH 2,6-Me.sub.2 -4-SMe-phenyl                            68 CH.sub.3                                                                               MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        NH 2,6-Me.sub.2 -4-OMe-phenyl                            69 CH.sub.3                                                                               MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        NH 2, 6-Me.sub.2 -4-SO.sub.2 Me-phenyl                   70 CH.sub.3                                                                               MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        NH 4-MeC(O)-2,6-Me.sub.2 -phenyl                         71 CH.sub.3                                                                               (MeOCH.sub.2).sub.2 CH                                                                    NH 4-Br-2,6-Me.sub.2 -phenyl                             72 CH.sub.3                                                                               (MeOCH.sub.2).sub.2 CH                                                                    NH 4-MeC(O)-2,6-Me.sub.2 -phenyl                         73 CH.sub.3                                                                               (MeOCH.sub.2).sub.2 CH                                                                    NH 2,6-Me.sub.2 -4-SMe-phenyl                            74 CH.sub.3                                                                               (MeOCH.sub.2).sub.2 CH                                                                    NH 2,6-Me.sub.2 -4-SO.sub.2 Me-phenyl                    75 CH.sub.3                                                                               (MeOCH.sub.2).sub.2 CH                                                                    NH 4-NMe.sub.2 -2,6-Me.sub.2 -phenyl                     76 CH.sub.3                                                                               (MeOCH.sub.2).sub.2 CH                                                                    NH 2-NMe.sub.2 -4,6-Me.sub.2 -phenyl                     77 Cl      MeOCH.sub.2 (Et)CH                                                                        NH 2,6-Me.sub.2 -4-SMe-phenyl                                                                    104.9                                  78 Cl      MeOCH.sub.2 (Et)CH                                                                        NH 2,6-Me.sub.2 -4-SO.sub.2 Me-phenyl                    79 Cl      MeOCH.sub.2 (Et)CH                                                                        NH 2-Cl-4,6-Me.sub.2 -phenyl                                                                     116.7                                  80 Cl      MeOCH.sub.2 (Et)CH                                                                        NH 4-Br-6-OMe-2-Me-phenyl                                                                        147.8                                  81 Cl      (MeOCH.sub.2).sub.2 CH                                                                    NH 2,6-Me.sub.2 -4-SMe-phenyl                                                                    158.9                                  82 Cl      (MeOCH.sub.2).sub.2 CH                                                                    NH 2,6-Me.sub.2 -4-SO.sub.2 Me-phenyl                    83 Cl      (MeOCH.sub.2).sub.2 CH                                                                    NH 4-Br-6-OMe-2-Me-phenyl                                                                        175.5                                  84 CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2,4,6-Me.sub.3 -phenyl                                                                        109                                    84a                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2-Cl-4,6-Me.sub.2 -phenyl                                                                     133.8                                  84b                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2-Cl-4-OMe-6-Me-phenyl                                                                        121.9                                  84c                                                                               CH.sub.2 CH.sub.3                                                                      Et.sub.2 CH                                                                               NH 2,4,6-Me.sub.3 -phenyl                                                                        79.3                                   84d                                                                               CH.sub.2 CH.sub.3                                                                      Et.sub.2 CH                                                                               NH 2-Cl-4,6-Me.sub.2 -phenyl                                                                     95.6                                   85 Br      Et.sub.2 CH                                                                               NH 2,4,6-Me.sub.3 -phenyl                                                                        MS = 378                               86 Br      Et.sub.2 CH                                                                               NH 2-Br-4-iPr-phenyl                                     87 Br      Et.sub.2 CH                                                                               NEt                                                                               2-Br-4-iPr-phenyl                                     88 Br      Et.sub.2 CH                                                                               NH 2,4-Br.sub.2 -phenyl                                  89 Br      Et.sub.2 CH                                                                               NEt                                                                               2,4-Br.sub.2 -phenyl                                  90 Br      Et.sub.2 CH                                                                               NEt                                                                               2,4,6-Me.sub.3 -phenyl                                91 Br      Et.sub.2 CH                                                                               NEt                                                                               2,4,6-Me.sub.3 -phenyl                                92 Br      MeOCH.sub.2 (Et)CH                                                                        NH 2,4,6-Me.sub.3 -phenyl                                93 Br      Et.sub.2 CH                                                                               NH 2-Br-4,6-(MeO).sub.2 -phenyl                          94 Br      Et.sub.2 CH                                                                               NH 2-CN-4,6-Me.sub.2 -phenyl                             95 Br      MeOCH.sub.2 (Et)CH                                                                        NH 2-Br-4,6-(MeO).sub.2 -phenyl                          96 Br      MeOCH.sub.2 (Et)CH                                                                        NH 2-I-4,6-Me.sub.2 -phenyl                              97 Br      MeOCH.sub.2 (Et)CH                                                                        NH 2,6-Me.sub.2 -4-Br-phenyl                             98 Br      MeOCH.sub.2 (Et)CH                                                                        NH 2-I-4-Cl-6-Me-phenyl                                  99 Br      (MeOCH.sub.2).sub.2 CH                                                                    NH 2,4,6-Me.sub.3 -phenyl                                100                                                                               Br      MeOCH.sub.2 (Et)CH                                                                        NH 2,6-Me2-4-SMe-phenyl                                  101                                                                               Br      MeOCH.sub.2 (Et)CH                                                                        NH 2,6-Me.sub.2 -4-SO.sub.2 Me-phenyl                    102                                                                               Br      MeOCH.sub.2 (Et)CH                                                                        NH 2-Cl-4,6-Me.sub.2 -phenyl                             103                                                                               Br      MeOCH.sub.2 (Et)CH                                                                        NH 2-Me-4-Br-6-OMe-phenyl                                104                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2,4,6-Me.sub.3 -pyrid-3-yl                            105                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 4,6-Me.sub.2 -pyrid-3-yl                              106                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2-Br-6-Me-pyrid-3-yl                                  107                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2-Br-6-OMe-pyrid-3-yl                                 108                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2,6-Me.sub.2 -pyrid-3-yl                              109                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2-Cl-6-Me-pyrid-3-yl                                  110                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2-Cl-6-OMe-pyrid-3-yl                                 111                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 2,4,6-Me.sub.3 -pyrid-3-yl                            112                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 4,6-Me.sub.2 -pyrid-3-yl                              113                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 2-Br-6-Me-pyrid-3-yl                                  114                                                                               CH.sub.3                                                                               (MeOCH.sub.2).sub.2 CH                                                                    NH 2-Br-6-OMe-pyrid-3-yl                                 115                                                                               CH.sub.3                                                                               (MeOCH.sub.2).sub.2 CH                                                                    NH 2,6-Me.sub.2 -pyrid-3-yl                              116                                                                               CH.sub.3                                                                               (MeOCH.sub.2).sub.2 CH                                                                    NH 2-Cl-6-Me-pyrid-3-yl                                  117                                                                               CH.sub.3                                                                               (MeOCH.sub.2).sub.2 CH                                                                    NH 2-Cl-6-OMe-pyrid-3-yl                                 118                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 2-Br-6-OMe-pyrid-3-yl                                 119                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 2,6-Me.sub.2 -pyrid-3-yl                              120                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 2-Cl-6-Me-pyrid-3-yl                                  121                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 2-Cl-6-OMe-pyrid-3-yl                                 120                                                                               CH.sub.3                                                                               (MeOCH.sub.2).sub.2 CH                                                                    NH 2,4,6-Me.sub.3 -pyrid-3-yl                            123                                                                               CH.sub.3                                                                               (MeOCH.sub.2).sub.2 CH                                                                    NH 4,6-Me.sub.2 -pyrid-3-yl                              124                                                                               CH.sub.3                                                                               (MeOCH.sub.2).sub.2 CH                                                                    NH 2-Br-6-Me-pyrid-3-yl                                  125                                                                               Cl      Et.sub.2 CH                                                                               NH 2-Br-6-OMe-pyrid-3-yl                                 124                                                                               Cl      Et.sub.2 CH                                                                               NH 2,6-Me.sub.2 -pyrid-3-yl                              127                                                                               Cl      Et.sub.2 CH                                                                               NH 2-Cl-6-Me-pyrid-3-yl                                  128                                                                               Cl      Et.sub.2 CH                                                                               NH 2-Cl-6-OMe-pyrid-3-yl                                 129                                                                               Cl      MeOCH.sub.2 (Et)CH                                                                        NH 2,4,6-Me.sub.3 -pyrid-3-yl                            130                                                                               Cl      MeOCH.sub.2 (Et)CH                                                                        NH 4,6-Me.sub.2 -pyrid-3-yl                              131                                                                               Cl      MeOCH.sub.2 (Et)CH                                                                        NH 2-Br-6-Me-pyrid-3-yl                                  132                                                                               Cl      Et.sub.2 CH                                                                               NH 2,4,6-Me.sub.3 -pyrid-3-yl                            133                                                                               Cl      Et.sub.2 CH                                                                               NH 4,6-Me.sub.2 -pyrid-3-yl                              134                                                                               Cl      Et.sub.2 CH                                                                               NH 2-Br-6-Me-pyrid-3-yl                                  135                                                                               Cl      MeOCH.sub.2 (Et)CH                                                                        NH 2-Br-6-OMe-pyrid-3-yl                                 136                                                                               Cl      MeOCH.sub.2 (Et)CH                                                                        NH 2,6-Me.sub.2 -pyrid-3-yl                              137                                                                               Cl      MeOCH.sub.2 (Et)CH                                                                        NH 2-Cl-6-Me-pyrid-3-yl                                  138                                                                               Cl      MeOCH.sub.2 (Et)CH                                                                        NH 2-Cl-6-OMe-pyrid-3-yl                                 139                                                                               Cl      (MeOCH.sub.2).sub.2 CH                                                                    NH 2-Br-6-OMe-pyrid-3-yl                                 140                                                                               Cl      (MeOCH.sub.2).sub.2 CH                                                                    NH 2,6-Me.sub.2 -pyrid-3-yl                              141                                                                               Cl      (MeOCH.sub.2).sub.2 CH                                                                    NH 2-Cl-6-Me-pyrid-3-yl                                  142                                                                               Cl      (MeOCH.sub.2).sub.2 CH                                                                    NH 2-Cl-6-OMe-pyrid-3-yl                                 143                                                                               Cl      (MeOCH.sub.2).sub.2 CH                                                                    NH 2,4,6-Me.sub.3 -pyrid-3-yl                            144                                                                               Cl      (MeOCH.sub.2).sub.2 CH                                                                    NH 4,6-Me.sub.2 -pyrid-3-yl                              145                                                                               Cl      (MeOCH.sub.2).sub.2 CH                                                                    NH 2-Br-6-Me-pyrid-3-yl                                  146                                                                               Et.sub.2 CH                                                                            CH.sub.3   NH 2,4,6-Me.sub.3 -phenyl                                147                                                                               Et.sub.2 CH                                                                            CH.sub.3   NH 2,6-Me.sub.2 -4-Br-phenyl                             148                                                                               Et.sub.2 CH                                                                            CH.sub.3   NH 2-Br-4-iPr-phenyl                                     149                                                                               MeOCH.sub.2 (Et)CH                                                                     CH.sub.3   NH 2,4,6-Me.sub.3 -phenyl                                150                                                                               MeOCH.sub.2 (Et)CH                                                                     CH.sub.3   NH 2,6-Me.sub.2 -4-Br-phenyl                             151                                                                               MeOCH.sub.2 (Et)CH                                                                     CH.sub.3   NH 2-Cl-4,6-Me.sub.2 -phenyl                             152                                                                               (MeOCH.sub.2).sub.2 CH                                                                 CH.sub.3   NH 2,4,6-Me.sub.3 -phenyl                                153                                                                               (MeOCH.sub.2).sub.2 CH                                                                 CH.sub.3   NH 2,6-Me.sub.2 -4-Br-phenyl                             154                                                                               (MeOCH.sub.2).sub.2 CH                                                                 CH.sub.3   NH 2-Cl-4,6-Me.sub.2 -phenyl                             155                                                                               Et.sub.2 CH                                                                            CH.sub.3   NH 2-Br-4,6-(MeO).sub.2 -phenyl                          156                                                                               Et.sub.2 CH                                                                            CH.sub.3   NH 2-Cl-4,6-Me.sub.2 -phenyl                             400                                                                               CH.sub.3                                                                               Me(Et)CH   NH 2,4,6-Me.sub.3 -phenyl                                401                                                                               CH.sub.3                                                                               Me(Et)CH   NH 2-Cl-4,6-Me.sub.2 -phenyl                             402                                                                               CH.sub.3                                                                               Me(Et)CH   NH 2,4-Cl.sub.2 -6-Me-phenyl                             403                                                                               CH.sub.3                                                                               Me(Et)CH   NH 2,4,6-Cl.sub.3 -phenyl                                404                                                                               CH.sub.3                                                                               Me(Et)CH   NH 2-Me-4-MeO-phenyl                                     405                                                                               CH.sub.3                                                                               Me(Et)CH   NH 2-Cl-4-MeO-phenyl                                     406                                                                               CH.sub.3                                                                               Me(Et)CH   NH 2,4,6-Me.sub.3 -5-F-phenyl                            407                                                                               CH.sub.3                                                                               Me(Et)CH   NH 2,5-Me.sub.2 -4-MeO-phenyl                            408                                                                               CH.sub.3                                                                               Me(Et)CH   NH 2,4-Me.sub.2 -6-MeO-phenyl                            409                                                                               CH.sub.3                                                                               Me(Et)CH   NH 2,6-Cl.sub.2 -4-Me-phenyl                             410                                                                               CH.sub.3                                                                               Me(Et)CH   NH 2,4-Cl.sub.2 -phenyl                                  411                                                                               CH.sub.3                                                                               Me(Et)CH   NH 2-Cl-4-Me-phenyl                                      412                                                                               CH.sub.3                                                                               Me(Et)CH   NH 2-Me-4-Cl-phenyl                                      413                                                                               CH.sub.3                                                                               Me(Et)CH   NH 2-NMe.sub.2 -6-Me-pyrid-5-yl                          414                                                                               CH.sub.3                                                                               Me(Et)CH   NH 2-NMe.sub.2 -4-Me-pyrid-5-yl                          415                                                                               CH.sub.3                                                                               Me(Et)CH   NH 2-Cl-4-MeO-6-Me-phenyl                                416                                                                               CH.sub.3                                                                               Me(Et)CH   NH 2-Cl-4,6-Me.sub.2 -5-F-phenyl                         417                                                                               CH.sub.3                                                                               Me(Et)CH   NH 6-Cl-2,3-dihydro-benzofuran-5-yl                      418                                                                               CH.sub.3                                                                               Me(Et)CH   NH 6-Me-2,3-dihydro-benzofuran-5-yl                      419                                                                               CH.sub.3                                                                               Me(n-Pr)CH NH 2,4,6-Me.sub.3 -phenyl                                420                                                                               CH.sub.3                                                                               Me(n-Pr)CH NH 2-Cl-4,6-Me.sub.2 -phenyl                             421                                                                               CH.sub.3                                                                               Me(n-Pr)CH NH 2,4-Cl.sub.2 -6-Me-phenyl                             422                                                                               CH.sub.3                                                                               Me(n-Pr)CH NH 2,4,6-Cl.sub.3 -phenyl                                423                                                                               CH.sub.3                                                                               Me(n-Pr)CH NH 2-Me-4-MeO-phenyl                                     424                                                                               CH.sub.3                                                                               Me(n-Pr)CH NH 2-Cl-4-MeO-phenyl                                     425                                                                               CH.sub.3                                                                               Me(n-Pr)CH NH 2,4,6-Me.sub.3 -5-F-phenyl                            426                                                                               CH.sub.3                                                                               Me(n-Pr)CH NH 2,5-Me.sub.2 -4-MeO-phenyl                            427                                                                               CH.sub.3                                                                               Me(n-Pr)CH NH 2,4-Me.sub.2 -6-MeO-phenyl                            428                                                                               CH.sub.3                                                                               Me(n-Pr)CH NH 2,6-Cl.sub.2 -4-Me-phenyl                             429                                                                               CH.sub.3                                                                               Me(n-Pr)CH NH 2,4-Cl.sub.2 -phenyl                                  430                                                                               CH.sub.3                                                                               Me(n-Pr)CH NH 2-Cl-4-Me-phenyl                                      431                                                                               CH.sub.3                                                                               Me(n-Pr)CH NH 2-Me-4-Cl-phenyl                                      432                                                                               CH.sub.3                                                                               Me(n-Pr)CH NH 2-NMe.sub.2 -6-Me-pyrid-5-yl                          433                                                                               CH.sub.3                                                                               Me(n-Pr)CH NH 2-NMe.sub.2 -4-Me-pyrid-5-yl                          434                                                                               CH.sub.3                                                                               Me(n-Pr)CH NH 2-Cl-4-MeO-6-Me-phenyl                                435                                                                               CH.sub.3                                                                               Me(n-Pr)CH NH 2-Cl-4,6-Me.sub.2 -5-F-phenyl                         436                                                                               CH.sub.3                                                                               Me(n-Pr)CH NH 6-Cl-2,3-dihydro-benzofuran-5-yl                      437                                                                               CH.sub.3                                                                               Me(n-Pr)CH NH 6-Me-2,3-dihydro-benzofuran-5-yl                      438                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2,4-Cl.sub.2 -6-Me-phenyl                             439                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2,4,6-Cl.sub.3 -phenyl                                440                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2-Me-4-MeO-phenyl                                     441                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2-Cl-4-MeO-phenyl                                     442                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2,4,6-Me.sub.3 -5-F-phenyl                            443                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2,5-Me.sub.2 -4-MeO-phenyl                            444                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2,4-Me.sub.2 -6-MeO-phenyl                            445                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2,6-Cl.sub.2 -4-Me-phenyl                             446                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2,4-Cl.sub.2 -phenyl                                  447                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2-Cl-4-Me-phenyl                                      448                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2-Me-4-Cl-phenyl                                      449                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2-NMe.sub.2 -6-Me-pyrid-5-yl                          450                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2-NMe.sub.2 -4-Me-pyrid-5-yl                          451                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2-Cl-4,6-Me.sub.2 -5-F-phenyl                         452                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 6-Cl-2,3-dihydro-benzofuran-5-yl                      453                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 6-Me-2,3-dihydro-benzofuran-5-yl                      454                                                                               CH.sub.3                                                                               (c-Pr).sub.2 CH                                                                           NH 2,4,6-Me.sub.3 -phenyl                                455                                                                               CH.sub.3                                                                               (c-Pr).sub.2 CH                                                                           NH 2-Cl-4,6-Me.sub.2 -phenyl                             456                                                                               CH.sub.3                                                                               (c-Pr).sub.2 CH                                                                           NH 2,4-Cl.sub.2 -6-Me-phenyl                             457                                                                               CH.sub.3                                                                               (c-Pr).sub.2 CH                                                                           NH 2,4,6-Cl.sub.3 -phenyl                                458                                                                               CH.sub.3                                                                               (c-Pr).sub.2 CH                                                                           NH 2-Me-4-MeO-phenyl                                     459                                                                               CH.sub.3                                                                               (c-Pr).sub.2 CH                                                                           NH 2-Cl-4-MeO-phenyl                                     460                                                                               CH.sub.3                                                                               (c-Pr).sub.2 CH                                                                           NH 2,4,6-Me.sub.3 -5-F-phenyl                            461                                                                               CH.sub.3                                                                               (c-Pr).sub.2 CH                                                                           NH 2,5-Me.sub.2 -4-MeO-phenyl                            462                                                                               CH.sub.3                                                                               (c-Pr).sub.2 CH                                                                           NH 2,4-Me.sub.2 -6-MeO-phenyl                            463                                                                               CH.sub.3                                                                               (c-Pr).sub.2 CH                                                                           NH 2,6-Cl.sub.2 -4-Me-phenyl                             464                                                                               CH.sub.3                                                                               (c-Pr).sub.2 CH                                                                           NH 2,4-Cl.sub.2 -phenyl                                  465                                                                               CH.sub.3                                                                               (c-Pr).sub.2 CH                                                                           NH 2-Cl-4-Me-phenyl                                      466                                                                               CH.sub.3                                                                               (c-Pr).sub.2 CH                                                                           NH 2-Me-4-Cl-phenyl                                      467                                                                               CH.sub.3                                                                               (c-Pr).sub.2 CH                                                                           NH 2-NMe.sub.2 -6-Me-pyrid-5-yl                          468                                                                               CH.sub.3                                                                               (c-Pr).sub.2 CH                                                                           NH 2-NMe.sub.2 -4-Me-pyrid-5-yl                          469                                                                               CH.sub.3                                                                               (c-Pr).sub.2 CH                                                                           NH 2-Cl-4-MeO-6-Me-phenyl                                470                                                                               CH.sub.3                                                                               (c-Pr).sub.2 CH                                                                           NH 2-Cl-4,6-Me.sub.2 -5-F-phenyl                         471                                                                               CH.sub.3                                                                               (c-Pr).sub.2 CH                                                                           NH 6-Cl-2,3-dihydro-benzofuran-5-yl                      472                                                                               CH.sub.3                                                                               (c-Pr).sub.2 CH                                                                           NH 6-Me-2,3-dihydro-benzofuran-5-yl                      473                                                                               CH.sub.3                                                                               c-Pr(Me)CH NH 2,4,6-Me.sub.3 -phenyl                                474                                                                               CH.sub.3                                                                               c-Pr(Me)CH NH 2-Cl-4,6-Me.sub.2 -phenyl                             475                                                                               CH.sub.3                                                                               c-Pr(Me)CH NH 2,4-Cl.sub.2 -6-Me-phenyl                             476                                                                               CH.sub.3                                                                               c-Pr(Me)CH NH 2,4,6-Cl.sub.3 -phenyl                                477                                                                               CH.sub.3                                                                               c-Pr(Me)CH NH 2-Me-4-MeO-phenyl                                     478                                                                               CH.sub.3                                                                               c-Pr(Me)CH NH 2-Cl-4-MeO-phenyl                                     479                                                                               CH.sub.3                                                                               c-Pr(Me)CH NH 2,4,6-Me.sub.3 -5-F-phenyl                            480                                                                               CH.sub.3                                                                               c-Pr(Me)CH NH 2,5-Me.sub.2 -4-MeO-phenyl                            481                                                                               CH.sub.3                                                                               c-Pr(Me)CH NH 2,4-Me.sub.2 -6-MeO-phenyl                            482                                                                               CH.sub.3                                                                               c-Pr(Me)CH NH 2,6-Cl.sub.2 -4-Me-phenyl                             483                                                                               CH.sub.3                                                                               c-Pr(Me)CH NH 2,4-Cl.sub.2 -phenyl                                  484                                                                               CH.sub.3                                                                               c-Pr(Me)CH NH 2-Cl-4-Me-phenyl                                      485                                                                               CH.sub.3                                                                               c-Pr(Me)CH NH 2-Me-4-Cl-phenyl                                      486                                                                               CH.sub.3                                                                               c-Pr(Me)CH NH 2-NMe.sub.2 -6-Me-pyrid-5-yl                          487                                                                               CH.sub.3                                                                               c-Pr(Me)CH NH 2-NMe.sub.2 -4-Me-pyrid-5-yl                          488                                                                               CH.sub.3                                                                               c-Pr(Me)CH NH 2-Cl-4-MeO-6-Me-phenyl                                489                                                                               CH.sub.3                                                                               c-Pr(Me)CH NH 2-Cl-4,6-Me.sub.2 -5-F-phenyl                         490                                                                               CH.sub.3                                                                               c-Pr(Me)CH NH 6-Cl-2,3-dihydro-benzofuran-5-yl                      491                                                                               CH.sub.3                                                                               c-Pr(Me)CH NH 6-Me-2,3-dihydro-benzofuran-5-yl                      492                                                                               CH.sub.3                                                                               c-Pr(Et)CH NH 2,4,6-Me.sub.3 -phenyl                                493                                                                               CH.sub.3                                                                               c-Pr(Et)CH NH 2-Cl-4,6-Me.sub.2 -phenyl                             494                                                                               CH.sub.3                                                                               c-Pr(Et)CH NH 2,4-Cl.sub.2 -6-Me-phenyl                             495                                                                               CH.sub.3                                                                               c-Pr(Et)CH NH 2,4,6-Cl.sub.3 -phenyl                                496                                                                               CH.sub.3                                                                               c-Pr(Et)CH NH 2-Me-4-MeO-phenyl                                     497                                                                               CH.sub.3                                                                               c-Pr(Et)CH NH 2-Cl-4-MeO-phenyl                                     498                                                                               CH.sub.3                                                                               c-Pr(Et)CH NH 2,4,6-Me.sub.3 -5-F-phenyl                            499                                                                               CH.sub.3                                                                               c-Pr(Et)CH NH 2,5-Me.sub.2 -4-MeO-phenyl                            500                                                                               CH.sub.3                                                                               c-Pr(Et)CH NH 2,4-Me.sub.2 -6-MeO-phenyl                            501                                                                               CH.sub.3                                                                               c-Pr(Et)CH NH 2,6-Cl.sub.2 -4-Me-phenyl                             502                                                                               CH.sub.3                                                                               c-Pr(Et)CH NH 2,4-Cl.sub.2 -phenyl                                  503                                                                               CH.sub.3                                                                               c-Pr(Et)CH NH 2-Cl-4-Me-phenyl                                      504                                                                               CH.sub.3                                                                               c-Pr(Et)CH NH 2-Me-4-Cl-phenyl                                      505                                                                               CH.sub.3                                                                               c-Pr(Et)CH NH 2-NMe.sub.2 -6-Me-pyrid-5-yl                          506                                                                               CH.sub.3                                                                               c-Pr(Et)CH NH 2-NMe.sub.2 -4-Me-pyrid-5-yl                          507                                                                               CH.sub.3                                                                               c-Pr(Et)CH NH 2-Cl-4-MeO-6-Me-phenyl                                508                                                                               CH.sub.3                                                                               c-Pr(Et)CH NH 2-Cl-4,6-Me.sub.2 -5-F-phenyl                         509                                                                               CH.sub.3                                                                               c-Pr(Et)CH NH 6-Cl-2,3-dihydro-benzofuran-5-yl                      510                                                                               CH.sub.3                                                                               c-Pr(Et)CH NH 6-Me-2,3-dihydro-benzofuran-5-yl                      511                                                                               CH.sub.3                                                                               c-Pr(n-Pr)CH                                                                              NH 2,4,6-Me.sub.3 -phenyl                                512                                                                               CH.sub.3                                                                               c-Pr(n-Pr)CH                                                                              NH 2-Cl-4,6-Me.sub.2 -phenyl                             513                                                                               CH.sub.3                                                                               c-Pr(n-Pr)CH                                                                              NH 2,4-Cl.sub.2 -6-Me-phenyl                             514                                                                               CH.sub.3                                                                               c-Pr(n-Pr)CH                                                                              NH 2,4,6-Cl.sub.3 -phenyl                                515                                                                               CH.sub.3                                                                               c-Pr(n-Pr)CH                                                                              NH 2-Me-4-MeO-phenyl                                     516                                                                               CH.sub.3                                                                               c-Pr(n-Pr)CH                                                                              NH 2-Cl-4-MeO-phenyl                                     517                                                                               CH.sub.3                                                                               c-Pr(n-Pr)CH                                                                              NH 2,4,6-Me.sub.3 -5-F-phenyl                            518                                                                               CH.sub.3                                                                               c-Pr(n-Pr)CH                                                                              NH 2,5-Me.sub.2 -4-MeO-phenyl                            519                                                                               CH.sub.3                                                                               c-Pr(n-Pr)CH                                                                              NH 2,4-Me.sub.2 -6-MeO-phenyl                            520                                                                               CH.sub.3                                                                               c-Pr(n-Pr)CH                                                                              NH 2,6-Cl.sub.2 -4-Me-phenyl                             521                                                                               CH.sub.3                                                                               c-Pr(n-Pr)CH                                                                              NH 2,4-Cl.sub.2 -phenyl                                  522                                                                               CH.sub.3                                                                               c-Pr(n-Pr)CH                                                                              NH 2-Cl-4-Me-phenyl                                      523                                                                               CH.sub.3                                                                               c-Pr(n-Pr)CH                                                                              NH 2-Me-4-Cl-phenyl                                      524                                                                               CH.sub.3                                                                               c-Pr(n-Pr)CH                                                                              NH 2-NMe.sub.2 -6-Me-pyrid-5-yl                          525                                                                               CH.sub.3                                                                               c-Pr(n-Pr)CH                                                                              NH 2-NMe.sub.2 -4-Me-pyrid-5-yl                          526                                                                               CH.sub.3                                                                               c-Pr(n-Pr)CH                                                                              NH 2-Cl-4-MeO-6-Me-phenyl                                527                                                                               CH.sub.3                                                                               c-Pr(n-Pr)CH                                                                              NH 2-Cl-4,6-Me.sub.2 -5-F-phenyl                         528                                                                               CH.sub.3                                                                               c-Pr(n-Pr)CH                                                                              NH 6-Cl-2,3-dihydro-benzofuran-5-yl                      529                                                                               CH.sub.3                                                                               c-Pr(n-Pr)CH                                                                              NH 6-Me-2,3-dihydro-benzofuran-5-yl                      530                                                                               CH.sub.3                                                                               c-Pr(n-Bu)CH                                                                              NH 2,4,6-Me.sub.3 -phenyl                                531                                                                               CH.sub.3                                                                               c-Pr(n-Bu)CH                                                                              NH 2-Cl-4,6-Me.sub.2 -phenyl                             532                                                                               CH.sub.3                                                                               c-Pr(n-Bu)CH                                                                              NH 2,4-Cl.sub.2 -6-Me-phenyl                             533                                                                               CH.sub.3                                                                               c-Pr(n-Bu)CH                                                                              NH 2,4,6-Cl.sub.3 -phenyl                                534                                                                               CH.sub.3                                                                               c-Pr(n-Bu)CH                                                                              NH 2-Me-4-MeO-phenyl                                     535                                                                               CH.sub.3                                                                               c-Pr(n-Bu)CH                                                                              NH 2-Cl-4-MeO-phenyl                                     536                                                                               CH.sub.3                                                                               c-Pr(n-Bu)CH                                                                              NH 2,4,6-Me.sub.3 -5-F-phenyl                            537                                                                               CH.sub.3                                                                               c-Pr(n-Bu)CH                                                                              NH 2,5-Me.sub.2 -4-MeO-phenyl                            538                                                                               CH.sub.3                                                                               c-Pr(n-Bu)CH                                                                              NH 2,4-Me.sub.2 -6-MeO-phenyl                            539                                                                               CH.sub.3                                                                               c-Pr(n-Bu)CH                                                                              NH 2,6-Cl.sub.2 -4-Me-phenyl                             540                                                                               CH.sub.3                                                                               c-Pr(n-Bu)CH                                                                              NH 2,4-Cl.sub.2 -phenyl                                  541                                                                               CH.sub.3                                                                               c-Pr(n-Bu)CH                                                                              NH 2-Cl-4-Me-phenyl                                      542                                                                               CH.sub.3                                                                               c-Pr(n-Bu)CH                                                                              NH 2-Me-4-Cl-phenyl                                      543                                                                               CH.sub.3                                                                               c-Pr(n-Bu)CH                                                                              NH 2-NMe.sub.2 -6-Me-pyrid-5-yl                          544                                                                               CH.sub.3                                                                               c-Pr(n-Bu)CH                                                                              NH 2-NMe.sub.2 -4-Me-pyrid-5-yl                          545                                                                               CH.sub.3                                                                               c-Pr(n-Bu)CH                                                                              NH 2-Cl-4-MeO-6-Me-phenyl                                546                                                                               CH.sub.3                                                                               c-Pr(n-Bu)CH                                                                              NH 2-Cl-4,6-Me.sub.2 -5-F-phenyl                         547                                                                               CH.sub.3                                                                               c-Pr(n-Bu)CH                                                                              NH 6-Cl-2,3-dihydro-benzofuran-5-yl                      548                                                                               CH.sub.3                                                                               c-Pr(n-Bu)CH                                                                              NH 6-Me-2,3-dihydro-benzofuran-5-yl                      549                                                                               CH.sub.3                                                                               c-PrCH.sub.2 (Et)CH                                                                       NH 2,4,6-Me.sub.3 -phenyl                                550                                                                               CH.sub.3                                                                               c-PrCH.sub.2 (Et)CH                                                                       NH 2-Cl-4,6-Me.sub.2 -phenyl                             551                                                                               CH.sub.3                                                                               c-PrCH.sub.2 (Et)CH                                                                       NH 2,4-Cl.sub.2 -6-Me-phenyl                             552                                                                               CH.sub.3                                                                               c-PrCH.sub.2 (Et)CH                                                                       NH 2,4,6-Cl.sub.3 -phenyl                                553                                                                               CH.sub.3                                                                               c-PrCH.sub.2 (Et)CH                                                                       NH 2-Me-4-MeO-phenyl                                     554                                                                               CH.sub.3                                                                               c-PrCH.sub.2 (Et)CH                                                                       NH 2-Cl-4-MeO-phenyl                                     555                                                                               CH.sub.3                                                                               c-PrCH.sub.2 (Et)CH                                                                       NH 2,4,6-Me.sub.3 -5-F-phenyl                            556                                                                               CH.sub.3                                                                               c-PrCH.sub.2 (Et)CH                                                                       NH 2,5-Me.sub.2 -4-MeO-phenyl                            557                                                                               CH.sub.3                                                                               c-PrCH.sub.2 (Et)CH                                                                       NH 2,4-Me.sub.2 -6-MeO-phenyl                            558                                                                               CH.sub.3                                                                               c-PrCH.sub.2 (Et)CH                                                                       NH 2,6-Cl.sub.2 -4-Me-phenyl                             559                                                                               CH.sub.3                                                                               c-PrCH.sub.2 (Et)CH                                                                       NH 2,4-Cl.sub.2 -phenyl                                  560                                                                               CH.sub.3                                                                               c-PrCH.sub.2 (Et)CH                                                                       NH 2-Cl-4-Me-phenyl                                      561                                                                               CH.sub.3                                                                               c-PrCH.sub.2 (Et)CH                                                                       NH 2-Me-4-Cl-phenyl                                      562                                                                               CH.sub.3                                                                               c-PrCH.sub.2 (Et)CH                                                                       NH 2-NMe.sub.2 -6-Me-pyrid-5-yl                          563                                                                               CH.sub.3                                                                               c-PrCH.sub.2 (Et)CH                                                                       NH 2-NMe.sub.2 -4-Me-pyrid-5-yl                          564                                                                               CH.sub.3                                                                               c-PrCH.sub.2 (Et)CH                                                                       NH 2-Cl-4-MeO-6-Me-phenyl                                565                                                                               CH.sub.3                                                                               c-PrCH.sub.2 (Et)CH                                                                       NH 2-Cl-4,6-Me.sub.2 -5-F-phenyl                         566                                                                               CH.sub.3                                                                               c-PrCH.sub.2 (Et)CH                                                                       NH 6-Cl-2,3-dihydro-benzofuran-5-yl                      567                                                                               CH.sub.3                                                                               c-PrCH.sub.2 (Et)CH                                                                       NH 6-Me-2,3-dihydro-benzofuran-5-yl                      __________________________________________________________________________

Compounds that can be synthesized using synthetic Scheme 6 or Scheme 7 are listed in Table 2

                                      TABLE 2                                      __________________________________________________________________________      ##STR11##                                                                     Ex.                                                                            No.                                                                               R.sup.1 R.sup.3    Y  Ar             mp                                     __________________________________________________________________________     200                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2,4-Br.sub.2 -phenyl                                  201                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2-Br-4-iPr-phenyl                                     202                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NEt                                                                               2,4-Br.sub.2 -phenyl                                  203                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NEt                                                                               2-Br-4-iPr-phenyl                                     204                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2,4,6-Me.sub.3 -phenyl                                                                        133                                    205                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NEt                                                                               2,4,6-Me.sub.3 -phenyl                                206                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 2,4,6-Me.sub.3 -phenyl                                207                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2-Br-4,6-(MeO).sub.2 -phenyl                          208                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 2-Br-4,6-(MeO).sub.2 -phenyl                          209                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 2-Cl-4,6-(MeO).sub.2 -phenyl                          210                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 2,4-Me.sub.2 -6-I-phenyl                              211                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 2-CN-4,6-Me.sub.2 -phenyl                             212                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 2-Br-4,6-Me.sub.2 -phenyl                             213                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 4-Br-2,6-Me.sub.2 -phenyl                             214                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 4-MeC(O)-2,6-Me.sub.2 -phenyl                         215                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 2-MeC(O)-4,6-Me.sub.2 -phenyl                         216                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 2,4-Me.sub.2 -6-SMe-phenyl                            217                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 2,4-Me.sub.2 -6-SO.sub.2 Me-phenyl                    218                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 4-Cl-2-I-6-Me-phenyl                                  219                                                                               CH.sub.3                                                                               (MeOCH.sub.2).sub.2 CH                                                                    NH 2,4,6-Me.sub.3 -phenyl                                220                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2,4,6-Me.sub.3 -phenyl                                221                                                                               CH.sub.3                                                                               (MeOCH.sub.2).sub.2 CH                                                                    NH 2,4-Cl.sub.2 -6-Me-phenyl                             222                                                                               CH.sub.3                                                                               (MeOCH.sub.2).sub.2 CH                                                                    NH 2,4-Br.sub.2 -6-Me-phenyl                             223                                                                               CH.sub.3                                                                               MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        NH 2,4,6-Me.sub.3 -phenyl                                224                                                                               CH.sub.3                                                                               (MeOC.sub.2 H.sub.4).sub.2 CH                                                             NH 2,4,6-Me.sub.3 -phenyl                                225                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 2,4-Me.sub.2 -6-MeO-phenyl                            226                                                                               CH.sub.3                                                                               MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        NH 2,4-Me.sub.2 -6-MeO-phenyl                            227                                                                               CH.sub.3                                                                               MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        NH 2-Br-4,6-Me.sub.2 -phenyl                             228                                                                               CH.sub.3                                                                               MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        NH 2-Cl-4,6-Me.sub.2 -phenyl                             229                                                                               CH.sub.3                                                                               MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        NH 2,4-Me.sub.2 -6-MeOCH.sub.2 -phenyl                   230                                                                               CH.sub.3                                                                               (MeOCH.sub.2).sub.2 CH                                                                    NH 2,4-Me.sub.2 -6-MeO-phenyl                            231                                                                               CH.sub.3                                                                               (MeOCH.sub.2).sub.2 CH                                                                    NH 4-Br-2,6-Me.sub.2 -phenyl                             232                                                                               CH.sub.3                                                                               (MeOCH.sub.2).sub.2 CH                                                                    NH 2-Cl-4,6-Me.sub.2 -phenyl                             233                                                                               CH.sub.3                                                                               (MeOCH.sub.2).sub.2 CH                                                                    NH 2,4-Me.sub.2 -6-MeOCH.sub.2 -phenyl                   234                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Me)CH                                                                        NH 2,4-Me.sub.2 -6-MeO-phenyl                            235                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Me)CH                                                                        NH 2-Br-4,6-Me.sub.2 -phenyl                             236                                                                               CH.sub.3                                                                               EtOCH.sub.2 (Et)CH                                                                        NH 2-Br-4,6-Me.sub.2 -phenyl                             237                                                                               CH.sub.3                                                                               EtOCH.sub.2 (Me)CH                                                                        NH 2-Br-4,6-Me.sub.2 -phenyl                             238                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 2-Br-4,6-F.sub.2 -phenyl                              239                                                                               Et.sub.2 CH                                                                            CH.sub.3   NH 2,4,6-Me.sub.3 -phenyl                                240                                                                               Et.sub.2 CH                                                                            CH.sub.3   NH 4-Br-2,6-Me.sub.2 -phenyl                             241                                                                               Et.sub.2 CH                                                                            CH.sub.3   NH 2-Br-4-iPr-phenyl                                     242                                                                               MeOCH.sub.2 (Et)CH                                                                     CH.sub.3   NH 2,4,6-Me.sub.3 -phenyl                                243                                                                               MeOCH.sub.2 (Et)CH                                                                     CH.sub.3   NH 4-Br-2,6-Me.sub.2 -phenyl                             244                                                                               MeOCH.sub.2 (Et)CH                                                                     CH.sub.3   NH 2-Cl-4,6-Me.sub.2 -phenyl                             245                                                                               (MeOCH.sub.2).sub.2 CH                                                                 CH.sub.3   NH 2,4,6-Me.sub.3 -phenyl                                246                                                                               (MeOCH.sub.2).sub.2 CH                                                                 CH.sub.3   NH 4-Br-2,6-Me.sub.2 -phenyl                             247                                                                               (MeOCH.sub.2).sub.2 CH                                                                 CH.sub.3   NH 2-Cl-4,6-Me.sub.2 -phenyl                             248                                                                               Et.sub.2 CH                                                                            CH.sub.3   NH 2-Br-4,6-(MeO).sub.2 -phenyl                          249                                                                               Et.sub.2 CH                                                                            CH.sub.3   NH 2-Cl-4,6-Me.sub.2 -phenyl                             250                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2-Cl-4,6-Me.sub.2 -phenyl                             251                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2,4-Cl.sub.2 -6-Me-phenyl                             252                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2,4,6-Cl.sub.3 -phenyl                                253                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2-Me-4-MeO-phenyl                                     254                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2-Cl-4-MeO-phenyl                                     255                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2,4,6-Me.sub.3 -5-F-phenyl                            256                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2,5-Me.sub.2 -4-MeO-phenyl                            257                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2,4-Me.sub.2 -6-MeO-phenyl                            258                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2,6-Cl.sub.2 -4-Me-phenyl                             259                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2,4-Cl.sub.2 -phenyl                                  260                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2-Cl-4-Me-phenyl                                      261                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2-Me-4-Cl-phenyl                                      262                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2-NMe.sub.2 -6-Me-pyrid-5-yl                          263                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2-NMe.sub.2 -4-Me-pyrid-5-yl                          264                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2-Cl-4-MeO-6-Me-phenyl                                265                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 2-Cl-4,6-Me.sub.2 -5-F-phenyl                         266                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 6-Cl-2,3-dihydro-benzofuran-5-yl                      267                                                                               CH.sub.3                                                                               Et.sub.2 CH                                                                               NH 6-Me-2,3-dihydro-benzofuran-5-yl                      268                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 2-Cl-4,6-Me.sub.2 -phenyl                             269                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 2,4-Cl.sub.2 -6-Me-phenyl                             270                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 2,4,6-Cl.sub.3 -phenyl                                271                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 2-Me-4-MeO-phenyl                                     272                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 2-Cl-4-MeO-phenyl                                     273                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 2,4,6-Me.sub.3 -5-F-phenyl                            274                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 2,5-Me.sub.2 -4-MeO-phenyl                            275                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 2,6-Cl.sub.2 -4-Me-phenyl                             276                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 2,4-Cl.sub.2 -phenyl                                  277                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 2-Cl-4-Me-phenyl                                      278                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 2-Me-4-Cl-phenyl                                      279                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 2-NMe.sub.2 -6-Me-pyrid-5-yl                          280                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 2-NMe.sub.2 -4-Me-pyrid-5-yl                          281                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 2-Cl-4-MeO-6-Me-phenyl                                282                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 2-Cl-4,6-Me.sub.2 -5-F-phenyl                         283                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 6-Cl-2,3-dihydro-benzofuran-5-yl                      284                                                                               CH.sub.3                                                                               MeOCH.sub.2 (Et)CH                                                                        NH 6-Me-2,3-dihydro-benzofuran-5-yl                      __________________________________________________________________________

Compounds wherein Y=Oxygen that can be synthesized using synthetic Scheme 3 are listed in Table 3

                                      TABLE 3                                      __________________________________________________________________________      ##STR12##                                                                     Ex                                                                             No R.sup.1                                                                           R.sup.3    Y Ar             mp/° C.                               __________________________________________________________________________     700                                                                               Cl Et.sub.2 CH                                                                               O 2-Br-4-iPr-phenyl                                           701                                                                               Cl Et.sub.2 CH                                                                               O 2,4-Br.sub.2 -phenyl                                        702                                                                               Cl Et.sub.2 CH                                                                               O 2,4,6-Me.sub.3 -phenyl                                      703                                                                               Cl MeOCH.sub.2 (Et)CH                                                                        O 2,4,6-Me.sub.3 -phenyl                                                                        116                                          704                                                                               Cl Et.sub.2 CH                                                                               O 2-Br-4,6-(MeO).sub.2 -phenyl                                705                                                                               Cl Et.sub.2 CH                                                                               O 2-CN-4,6-Me.sub.2 -phenyl                                   706                                                                               Cl MeOCH.sub.2 (Et)CH                                                                        O 2-Br-4,6-(MeO).sub.2 -phenyl                                707                                                                               Cl MeOCH.sub.2 (Et)CH                                                                        O 2-Cl-4,6-(MeO).sub.2 -phenyl                                708                                                                               Cl MeOCH.sub.2 (Et)CH                                                                        O 2-I-4,6-Me.sub.2 -phenyl                                    709                                                                               Cl MeOCH.sub.2 (Et)CH                                                                        O 2-CN-4,6-Me.sub.2 -phenyl                                   710                                                                               Cl MeOCH.sub.2 (Et)CH                                                                        O 2-Br-4,6-Me.sub.2 -phenyl                                   711                                                                               Cl MeOCH.sub.2 (Et)CH                                                                        O 4-Br-2,6-Me.sub.2 -phenyl                                   712                                                                               Cl MeOCH.sub.2 (Et)CH                                                                        O 4-MeCO-2,6-Me.sub.2 -phenyl                                 713                                                                               Cl MeOCH.sub.2 (Et)CH                                                                        O 4-MeCO-2-OMe-6-Me-phenyl                                    714                                                                               Cl MeOCH.sub.2 (Et)CH                                                                        O 2-MeCO-4,6-Me.sub.2 -phenyl                                 715                                                                               Cl MeOCH.sub.2 (Et)CH                                                                        O 4,6-Me.sub.2 -2-SMe-phenyl                                  716                                                                               Cl MeOCH.sub.2 (Et)CH                                                                        O 4,6-Me.sub.2 -2-SO.sub.2 Me-phenyl                          717                                                                               Cl MeOCH.sub.2 (Et)CH                                                                        O 4-Cl-2-I-6-Me-phenyl                                        718                                                                               Cl (MeOCH.sub.2).sub.2 CH                                                                    O 2,4,6-Me.sub.3 -phenyl                                      719                                                                               Cl phenyl     O 2,4,6-Me.sub.3 -phenyl                                      720                                                                               CH.sub.3                                                                          MeOCH.sub.2 (Et)CH                                                                        O 2,4-Br.sub.2 -phenyl                                        721                                                                               CH.sub.3                                                                          MeOCH.sub.2 (Et)CH                                                                        O 2-Br-4-iPr-phenyl                                           722                                                                               CH.sub.3                                                                          MeOCH.sub.2 (Et)CH                                                                        O 2,4,6-Me.sub.3 -phenyl                                      723                                                                               CH.sub.3                                                                          MeOCH.sub.2 (Et)CH                                                                        O 2-Cl-4,6-Me.sub.2 -phenyl                                   724                                                                               CH.sub.3                                                                          (MeOCH.sub.2).sub.2 CH                                                                    O 2,4,6-Me.sub.3 -phenyl                                      725                                                                               CH.sub.3                                                                          (MeOCH.sub.2).sub.2 CH                                                                    O 2,4-Cl.sub.2 -6-Me-phenyl                                   726                                                                               Cl (MeOCH.sub.2).sub.2 CH                                                                    O 2,4-Cl.sub.2 -6-Me-phenyl                                   727                                                                               Cl (MeOCH.sub.2).sub.2 CH                                                                    O 2,4-Br.sub.2 -6-Me-phenyl                                   728                                                                               CH.sub.3                                                                          MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        O 2,4,6-Me.sub.3 -phenyl                                      729                                                                               Cl MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        O 2,4,6-Me.sub.3 -phenyl                                      730                                                                               Cl MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        O 4-Br-2-OMe-6-Me-phenyl                                      731                                                                               Cl (MeOC.sub.2 H.sub.4).sub.2 CH                                                             O 2,4,6-Me.sub.3 -phenyl                                      732                                                                               Cl MeOCH.sub.2 (Et)CH                                                                        O 2,4-Me.sub.2 -6-MeO-phenyl                                  733                                                                               Cl MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        O 2,4-Me.sub.2 -6-MeO-phenyl                                  734                                                                               CH.sub.3                                                                          MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        O 2,4-Me.sub.2 -6-MeO-phenyl                                  735                                                                               CH.sub.3                                                                          MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        0 4-Br-2,6-Me.sub.2 -phenyl                                   736                                                                               CH.sub.3                                                                          MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        O 2-Cl-4,6-Me.sub.2 -phenyl                                   737                                                                               CH.sub.3                                                                          MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        O 2,4-Me.sub.2 -6-MeOCH.sub.2 -phenyl                         738                                                                               CH.sub.3                                                                          (MeOCH.sub.2).sub.2 CH                                                                    O 2,4-Me.sub.2 -6-MeO-phenyl                                  739                                                                               CH.sub.3                                                                          (MeOCH.sub.2).sub.2 CH                                                                    O 4-Br-2,6-Me.sub.2 -phenyl                                   740                                                                               CH.sub.3                                                                          (MeOCH.sub.2).sub.2 CH                                                                    O 2-Br-6-F-4-Me-phenyl                                        741                                                                               CH.sub.3                                                                          (MeOCH.sub.2).sub.2 CH                                                                    O 2-Cl-4,6-Me.sub.2 -phenyl                                   742                                                                               CH.sub.3                                                                          (MeOCH.sub.2).sub.2 CH                                                                    O 2-Cl-4-OMe-6-Me-phenyl                                      743                                                                               CH.sub.3                                                                          (MeOCH.sub.2).sub.2 CH                                                                    O 2,4-Me.sub.2 -6-MeOCH.sub.2 -phenyl                         744                                                                               Cl MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        O 2,4-Me.sub.2 -6-MeO-phenyl                                  745                                                                               Cl MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        O 4-Br-2,6-Me.sub.2 -phenyl                                   746                                                                               Cl MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        O 2-Cl-4,6-Me.sub.2 -phenyl                                   747                                                                               Cl MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        O 2,4-Me.sub.2 -6-MeOCH.sub.2 -phenyl                         748                                                                               Cl (MeOCH.sub.2).sub.2 CH                                                                    O 2,4-Me.sub.2 -6-MeO-phenyl                                  749                                                                               Cl (MeOCH.sub.2).sub.2 CH                                                                    O 4-Br-2,6-Me.sub.2 -phenyl                                   750                                                                               Cl (MeOCH.sub.2).sub.2 CH                                                                    O 2-Cl-4,6-Me.sub.2 -phenyl                                   751                                                                               Cl (MeOCH.sub.2).sub.2 CH                                                                    O 2,4-Me.sub.2 -6-MeOCH.sub.2 -phenyl                         752                                                                               Cl MeOCH.sub.2 (Me)CH                                                                        O 2,4-Me.sub.2 -6-MeO-phenyl                                  753                                                                               Cl MeOCH.sub.2 (Me)CH                                                                        O 4-Br-2,6-Me.sub.2 -phenyl                                   754                                                                               Cl EtOCH.sub.2 (Et)CH                                                                        O 4-Br-2,6-Me.sub.2 -phenyl                                   755                                                                               Cl EtOCH.sub.2 (Me)CH                                                                        O 4-Br-2,6-Me.sub.2 -phenyl                                   756                                                                               Cl MeOCH.sub.2 (Et)CH                                                                        O 4-Br-2,6-F.sub.2 -phenyl                                    757                                                                               CH.sub.3                                                                          MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        O 2-Br-4,6-Me.sub.2 -phenyl                                   758                                                                               CH.sub.3                                                                          MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        O 2,4-Me.sub.2 -6-SMe-phenyl                                  759                                                                               CH.sub.3                                                                          MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        O 2,4-Me.sub.2 -6-SO.sub.2 Me-phenyl                          760                                                                               CH.sub.3                                                                          MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        O 4-NMe.sub.2 -2,6-Me.sub.2 -phenyl                           761                                                                               CH.sub.3                                                                          MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        O 2,4-Cl.sub.2 -6-Me-phenyl                                   762                                                                               CH.sub.3                                                                          MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        O 4-Cl-2,6-Me.sub.2 -phenyl                                   763                                                                               CH.sub.3                                                                          MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        O 2,6-Me.sub.2 -4-SMe-phenyl                                  764                                                                               CH.sub.3                                                                          MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        O 2,6-Me.sub.2 -4-OMe-phenyl                                  765                                                                               CH.sub.3                                                                          MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        O 2,6-Me.sub.2 -4-SO.sub.2 Me-phenyl                          766                                                                               CH.sub.3                                                                          MeOC.sub.2 H.sub.4 (MeOCH.sub.2)CH                                                        O 4-MeC(O)-2,6-Me.sub.2 -phenyl                               767                                                                               CH.sub.3                                                                          (MeOCH.sub.2).sub.2 CH                                                                    O 4-Br-2,6-Me.sub.2 -phenyl                                   768                                                                               CH.sub.3                                                                          (MeOCH.sub.2).sub.2 CH                                                                    O 4-MeC(O)-2,6-Me.sub.2 -phenyl                               769                                                                               CH.sub.3                                                                          (MeOCH.sub.2).sub.2 CH                                                                    O 2,6-Me.sub.2 -4-SMe-phenyl                                  770                                                                               CH.sub.3                                                                          (MeOCH.sub.2).sub.2 CH                                                                    O 2,6-Me.sub.2 -4-SO.sub.2 Me-phenyl                          771                                                                               CH.sub.3                                                                          (MeOCH.sub.2).sub.2 CH                                                                    O 4-NMe.sub.2 -2,6-Me.sub.2 -phenyl                           772                                                                               CH.sub.3                                                                          (MeOCH.sub.2).sub.2 CH                                                                    O 2-NMe.sub.2 -4,6-Me.sub.2 -phenyl                           773                                                                               Cl MeOCH.sub.2 (Et)CH                                                                        O 2,6-Me.sub.2 -4-SMe-phenyl                                  774                                                                               Cl MeOCH.sub.2 (Et)CH                                                                        O 2,6-Me.sub.2 -4-SO.sub.2 Me-phenyl                          775                                                                               Cl MeOCH.sub.2 (Et)CH                                                                        O 2-Cl-4,6-Me.sub.2 -phenyl                                   776                                                                               Cl MeOCH.sub.2 (Et)CH                                                                        O 4-Br-6-OMe-2-Me-phenyl                                      777                                                                               Cl (MeOCH.sub.2).sub.2 CH                                                                    O 2,6-Me.sub.2 -4-SMe-phenyl                                  778                                                                               Cl (MeOCH.sub.2).sub.2 CH                                                                    O 2,6-Me.sub.2 -4-SO.sub.2 Me-phenyl                          779                                                                               Cl (MeOCH.sub.2).sub.2 CH                                                                    O 4-Br-6-OMe-2-Me-phenyl                                      780                                                                               CH.sub.3                                                                          Et.sub.2 CH                                                                               O 2,4,6-Me.sub.3 -phenyl                                      781                                                                               CH.sub.3                                                                          Et.sub.2 CH                                                                               O 2-Cl-4,6-Me.sub.2 -phenyl                                   782                                                                               CH.sub.3                                                                          Et.sub.2 CH                                                                               O 2-Cl-4-OMe-6-Me-phenyl                                      783                                                                               CH.sub.3                                                                          Et.sub.2 CH                                                                               O 2,4,6-Me.sub.3 -pyrid-3-yl                                  784                                                                               CH.sub.3                                                                          Et.sub.2 CH                                                                               O 4,6-Me.sub.2 -pyrid-3-yl                                    785                                                                               CH.sub.3                                                                          Et.sub.2 CH                                                                               O 2-Br-6-Me-pyrid-3-yl                                        786                                                                               CH.sub.3                                                                          Et.sub.2 CH                                                                               O 2-Br-6-OMe-pyrid-3-yl                                       787                                                                               CH.sub.3                                                                          Et.sub.2 CH                                                                               O 2,6-Me.sub.2 -pyrid-3-yl                                    788                                                                               CH.sub.3                                                                          Et.sub.2 CH                                                                               O 2-Cl-6-Me-pyrid-3-yl                                        789                                                                               CH.sub.3                                                                          Et.sub.2 CH                                                                               O 2-Cl-6-OMe-pyrid-3-yl                                       790                                                                               CH.sub.3                                                                          MeOCH.sub.2 (Et)CH                                                                        O 2,4,6-Me.sub.3 -pyrid-3-yl                                  791                                                                               CH.sub.3                                                                          MeOCH.sub.2 (Et)CH                                                                        O 4,6-Me.sub.2 -pyrid-3-yl                                    792                                                                               CH.sub.3                                                                          MeOCH.sub.2 (Et)CH                                                                        O 2-Br-6-Me-pyrid-3-yl                                        793                                                                               CH.sub.3                                                                          (MeOCH.sub.2).sub.2 CH                                                                    O 2-Br-6-OMe-pyrid-3-yl                                       794                                                                               CH.sub.3                                                                          (MeOCH.sub.2).sub.2 CH                                                                    O 2,6-Me.sub.2 -pyrid-3-yl                                    795                                                                               CH.sub.3                                                                          (MeOCH.sub.2).sub.2 CH                                                                    O 2-Cl-6-Me-pyrid-3-yl                                        796                                                                               CH.sub.3                                                                          (MeOCH.sub.2).sub.2 CH                                                                    O 2-Cl-6-OMe-pyrid-3-yl                                       797                                                                               CH.sub.3                                                                          MeOCH.sub.2 (Et)CH                                                                        O 2-Br-6-OMe-pyrid-3-yl                                       798                                                                               CH.sub.3                                                                          MeOCH.sub.2 (Et)CH                                                                        O 2,6-Me.sub.2 -pyrid-3-yl                                    799                                                                               CH.sub.3                                                                          MeOCH.sub.2 (Et)CH                                                                        O 2-Cl-6-Me-pyrid-3-yl                                        800                                                                               CH.sub.3                                                                          MeOCH.sub.2 (Et)CH                                                                        O 2-Cl-6-OMe-pyrid-3-yl                                       801                                                                               CH.sub.3                                                                          (MeOCH.sub.2).sub.2 CH                                                                    O 2,4,6-Me.sub.3 -pyrid-3-yl                                  802                                                                               CH.sub.3                                                                          (MeOCH.sub.2).sub.2 CH                                                                    O 4,6-Me.sub.2 -pyrid-3-yl                                    803                                                                               CH.sub.3                                                                          (MeOCH.sub.2).sub.2 CH                                                                    O 2-Br-6-Me-pyrid-3-yl                                        804                                                                               Cl Et.sub.2 CH                                                                               O 2-Br-6-OMe-pyrid-3-yl                                       805                                                                               Cl Et.sub.2 CH                                                                               O 2,6-Me.sub.2 -pyrid-3-yl                                    806                                                                               Cl Et.sub.2 CH                                                                               O 2-Cl-6-Me-pyrid-3-yl                                        807                                                                               Cl Et.sub.2 CH                                                                               O 2-Cl-6-OMe-pyrid-3-yl                                       808                                                                               Cl MeOCH.sub.2 (Et)CH                                                                        O 2,4,6-Me.sub.3 -pyrid-3-yl                                  809                                                                               Cl MeOCH.sub.2 (Et)CH                                                                        O 4,6-Me.sub.2 -pyrid-3-yl                                    810                                                                               Cl MeOCH.sub.2 (Et)CH                                                                        O 2-Br-6-Me-pyrid-3-yl                                        811                                                                               Cl Et.sub.2 CH                                                                               O 2,4,6-Me.sub.3 -pyrid-3-yl                                  812                                                                               Cl Et.sub.2 CH                                                                               O 4,6-Me.sub.2 -pyrid-3-yl                                    813                                                                               Cl Et.sub.2 CH                                                                               O 2-Br-6-Me-pyrid-3-yl                                        814                                                                               Cl MeOCH.sub.2 (Et)CH                                                                        O 2-Br-6-OMe-pyrid-3-yl                                       815                                                                               Cl MeOCH.sub.2 (Et)CH                                                                        O 2,6-Me.sub.2 -pyrid-3-yl                                    816                                                                               Cl MeOCH.sub.2 (Et)CH                                                                        O 2-Cl-6-Me-pyrid-3-yl                                        817                                                                               Cl MeOCH.sub.2 (Et)CH                                                                        O 2-Cl-6-OMe-pyrid-3-yl                                       818                                                                               Cl (MeOCH.sub.2).sub.2 CH                                                                    O 2-Br-6-OMe-pyrid-3-yl                                       819                                                                               Cl (MeOCH.sub.2).sub.2 CH                                                                    O 2,6-Me.sub.2 -pyrid-3-yl                                    820                                                                               Cl (MeOCH.sub.2).sub.2 CH                                                                    O 2-Cl-6-Me-pyrid-3-yl                                        821                                                                               Cl (MeOCH.sub.2).sub.2 CH                                                                    O 2-Cl-6-OMe-pyrid-3-yl                                       822                                                                               Cl (MeOCH.sub.2).sub.2 CH                                                                    O 2,4,6-Me.sub.3 -pyrid-3-yl                                  823                                                                               Cl (MeOCH.sub.2).sub.2 CH                                                                    O 4,6-Me.sub.2 -pyrid-3-yl                                    824                                                                               Cl (MeOCH.sub.2).sub.2 CH                                                                    O 2-Br-6-Me-pyrid-3-yl                                        825                                                                               CH.sub.3                                                                          Me(Et)CH   O 2,4,6-Me.sub.3 -phenyl                                      826                                                                               CH.sub.3                                                                          Me(Et)CH   O 2-Cl-4,6-Me.sub.2 -phenyl                                   827                                                                               CH.sub.3                                                                          Me(Et)CH   O 2,4-Cl.sub.2 -6-Me-phenyl                                   828                                                                               CH.sub.3                                                                          Me(Et)CH   O 2,4,6-Cl.sub.3 -phenyl                                      829                                                                               CH.sub.3                                                                          Me(Et)CH   O 2-Me-4-MeO-phenyl                                           830                                                                               CH.sub.3                                                                          Me(Et)CH   O 2-Cl-4-MeO-phenyl                                           831                                                                               CH.sub.3                                                                          Me(Et)CH   O 2,4,6-Me.sub.3 -5-F-phenyl                                  832                                                                               CH.sub.3                                                                          Me(Et)CH   O 2,5-Me.sub.2 -4-MeO-phenyl                                  833                                                                               CH.sub.3                                                                          Me(Et)CH   O 2,4-Me.sub.2 -6-MeO-phenyl                                  834                                                                               CH.sub.3                                                                          Me(Et)CH   O 2,6-Cl.sub.2 -4-Me-phenyl                                   835                                                                               CH.sub.3                                                                          Me(Et)CH   O 2,4-Cl.sub.2 -phenyl                                        836                                                                               CH.sub.3                                                                          Me(Et)CH   O 2-Cl-4-Me-phenyl                                            837                                                                               CH.sub.3                                                                          Me(Et)CH   O 2-Me-4-Cl-phenyl                                            838                                                                               CH.sub.3                                                                          Me(Et)CH   O 2-NMe.sub.2 -6-Me-pyrid-5-yl                                839                                                                               CH.sub.3                                                                          Me(Et)CH   O 2-NMe.sub.2 -4-Me-pyrid-5-yl                                840                                                                               CH.sub.3                                                                          Me(Et)CH   O 2-Cl-4-MeO-6-Me-phenyl                                      841                                                                               CH.sub.3                                                                          Me(Et)CH   O 2-Cl-4,6-Me.sub.2 -5-F-phenyl                               842                                                                               CH.sub.3                                                                          Me(Et)CH   O 6-Cl-2,3-dihydro-benzofuran-5-yl                            843                                                                               CH.sub.3                                                                          Me(Et)CH   O 6-Me-2,3-dihydro-benzofuran-5-yl                            844                                                                               CH.sub.3                                                                          Me(n-Pr)CH O 2,4,6-Me.sub.3 -phenyl                                      845                                                                               CH.sub.3                                                                          Me(n-Pr)CH O 2-Cl-4,6-Me.sub.2 -phenyl                                   846                                                                               CH.sub.3                                                                          Me(n-Pr)CH O 2,4-Cl.sub.2 -6-Me-phenyl                                   847                                                                               CH.sub.3                                                                          Me(n-Pr)CH O 2,4,6-Cl.sub.3 -phenyl                                      848                                                                               CH.sub.3                                                                          Me(n-Pr)CH O 2-Me-4-MeO-phenyl                                           849                                                                               CH.sub.3                                                                          Me(n-Pr)CH O 2-Cl-4-MeO-phenyl                                           850                                                                               CH.sub.3                                                                          Me(n-Pr)CH O 2,4,6-Me.sub.3 -5-F-phenyl                                  851                                                                               CH.sub.3                                                                          Me(n-Pr)CH O 2,5-Me.sub.2 -4-MeO-phenyl                                  852                                                                               CH.sub.3                                                                          Me(n-Pr)CH O 2,4-Me.sub.2 -6-MeO-phenyl                                  853                                                                               CH.sub.3                                                                          Me(n-Pr)CH O 2,6-Cl.sub.2 -4-Me-phenyl                                   854                                                                               CH.sub.3                                                                          Me(n-Pr)CH O 2,4-Cl.sub.2 -phenyl                                        855                                                                               CH.sub.3                                                                          Me(n-Pr)CH O 2-Cl-4-Me-phenyl                                            856                                                                               CH.sub.3                                                                          Me(n-Pr)CH O 2-Me-4-Cl-phenyl                                            857                                                                               CH.sub.3                                                                          Me(n-Pr)CH O 2-NMe.sub.2 -6-Me-pyrid-5-yl                                858                                                                               CH.sub.3                                                                          Me(n-Pr)CH O 2-NMe.sub.2 -4-Me-pyrid-5-yl                                859                                                                               CH.sub.3                                                                          Me(n-Pr)CH O 2-Cl-4-MeO-6-Me-phenyl                                      860                                                                               CH.sub.3                                                                          Me(n-Pr)CH O 2-Cl-4,6-Me.sub.2 -5-F-phenyl                               861                                                                               CH.sub.3                                                                          Me(n-Pr)CH O 6-Cl-2,3-dihydro-benzofuran-5-yl                            862                                                                               CH.sub.3                                                                          Me(n-Pr)CH O 6-Me-2,3-dihydro-benzofuran-5-yl                            863                                                                               CH.sub.3                                                                          c-Pr.sub.2 CH                                                                             O 2,4,6-Me.sub.3 -phenyl                                      864                                                                               CH.sub.3                                                                          c-Pr.sub.2 CH                                                                             O 2-Cl-4,6-Me.sub.2 -phenyl                                   865                                                                               CH.sub.3                                                                          c-Pr.sub.2 CH                                                                             O 2,4-Cl.sub.2 -6-Me-phenyl                                   866                                                                               CH.sub.3                                                                          c-Pr.sub.2 CH                                                                             O 2,4,6-Cl.sub.3 -phenyl                                      867                                                                               CH.sub.3                                                                          c-Pr.sub.2 CH                                                                             O 2-Me-4-MeO-phenyl                                           868                                                                               CH.sub.3                                                                          c-Pr.sub.2 CH                                                                             O 2-Cl-4-MeO-phenyl                                           869                                                                               CH.sub.3                                                                          c-Pr.sub.2 CH                                                                             O 2,4,6-Me.sub.3 -5-F-phenyl                                  870                                                                               CH.sub.3                                                                          c-Pr.sub.2 CH                                                                             O 2,5-Me.sub.2 -4-MeO-phenyl                                  871                                                                               CH.sub.3                                                                          c-Pr.sub.2 CH                                                                             O 2,4-Me.sub.2 -6-MeO-phenyl                                  872                                                                               CH.sub.3                                                                          c-Pr.sub.2 CH                                                                             O 2,6-Cl.sub.2 -4-Me-phenyl                                   873                                                                               CH.sub.3                                                                          c-Pr.sub.2 CH                                                                             O 2,4-Cl.sub.2 -phenyl                                        874                                                                               CH.sub.3                                                                          c-Pr.sub.2 CH                                                                             O 2-Cl-4-Me-phenyl                                            875                                                                               CH.sub.3                                                                          c-Pr.sub.2 CH                                                                             O 2-Me-4-Cl-phenyl                                            876                                                                               CH.sub.3                                                                          c-Pr.sub.2 CH                                                                             O 2-NMe.sub.2 -6-Me-pyrid-5-yl                                877                                                                               CH.sub.3                                                                          c-Pr.sub.2 CH                                                                             O 2-NMe.sub.2 -4-Me-pyrid-5-yl                                878                                                                               CH.sub.3                                                                          c-Pr.sub.2 CH                                                                             O 2-Cl-4-MeO-6-Me-phenyl                                      879                                                                               CH.sub.3                                                                          c-Pr.sub.2 CH                                                                             O 2-Cl-4,6-Me.sub.2 -5-F-phenyl                               880                                                                               CH.sub.3                                                                          c-Pr.sub.2 CH                                                                             O 6-Cl-2,3-dihydro-benzofuran-5-yl                            881                                                                               CH.sub.3                                                                          c-Pr.sub.2 CH                                                                             O 6-Me-2,3-dihydro-benzofuran-5-yl                            882                                                                               CH.sub.3                                                                          c-Pr(Me)CH O 2,4,6-Me.sub.3 -phenyl                                      883                                                                               CH.sub.3                                                                          c-Pr(Me)CH O 2-Cl-4,6-Me.sub.2 -phenyl                                   884                                                                               CH.sub.3                                                                          c-Pr(Me)CH O 2,4-Cl.sub.2 -6-Me-phenyl                                   885                                                                               CH.sub.3                                                                          c-Pr(Me)CH O 2,4,6-Cl.sub.3 -phenyl                                      886                                                                               CH.sub.3                                                                          c-Pr(Me)CH O 2-Me-4-MeO-phenyl                                           887                                                                               CH.sub.3                                                                          c-Pr(Me)CH O 2-Cl-4-MeO-phenyl                                           888                                                                               CH.sub.3                                                                          c-Pr(Me)CH O 2,4,6-Me.sub.3 -5-F-phenyl                                  889                                                                               CH.sub.3                                                                          c-Pr(Me)CH O 2,5-Me.sub.2 -4-MeO-phenyl                                  890                                                                               CH.sub.3                                                                          c-Pr(Me)CH O 2,4-Me.sub.2 -6-MeO-phenyl                                  891                                                                               CH.sub.3                                                                          c-Pr(Me)CH O 2,6-Cl.sub.2 -4-Me-phenyl                                   892                                                                               CH.sub.3                                                                          c-Pr(Me)CH O 2,4-Cl.sub.2 -phenyl                                        893                                                                               CH.sub.3                                                                          c-Pr(Me)CH O 2-Cl-4-Me-phenyl                                            894                                                                               CH.sub.3                                                                          c-Pr(Me)CH O 2-Me-4-Cl-phenyl                                            895                                                                               CH.sub.3                                                                          c-Pr(Me)CH O 2-NMe.sub.2 -6-Me-pyrid-5-yl                                896                                                                               CH.sub.3                                                                          c-Pr(Me)CH O 2-NMe.sub.2 -4-Me-pyrid-5-yl                                897                                                                               CH.sub.3                                                                          c-Pr(Me)CH O 2-Cl-4-MeO-6-Me-phenyl                                      898                                                                               CH.sub.3                                                                          c-Pr(Me)CH O 2-Cl-4,6-Me.sub.2 -5-F-phenyl                               899                                                                               CH.sub.3                                                                          c-Pr(Me)CH O 6-Cl-2,3-dihydro-benzofuran-5-yl                            900                                                                               CH.sub.3                                                                          c-Pr(Me)CH O 6-Me-2,3-dihydro-benzofuran-5-yl                            901                                                                               CH.sub.3                                                                          c-Pr(Et)CH O 2,4,6-Me.sub.3 -phenyl                                      902                                                                               CH.sub.3                                                                          c-Pr(Et)CH O 2-Cl-4,6-Me.sub.2 -phenyl                                   903                                                                               CH.sub.3                                                                          c-Pr(Et)CH O 2,4-Cl.sub.2 -6-Me-phenyl                                   904                                                                               CH.sub.3                                                                          c-Pr(Et)CH O 2,4,6-Cl.sub.3 -phenyl                                      905                                                                               CH.sub.3                                                                          c-Pr(Et)CH O 2-Me-4-MeO-phenyl                                           906                                                                               CH.sub.3                                                                          c-Pr(Et)CH O 2-Cl-4-MeO-phenyl                                           907                                                                               CH.sub.3                                                                          c-Pr(Et)CH O 2,4,6-Me.sub.3 -5-F-phenyl                                  908                                                                               CH.sub.3                                                                          c-Pr(Et)CH O 2,5-Me.sub.2 -4-MeO-phenyl                                  909                                                                               CH.sub.3                                                                          c-Pr(Et)CH O 2,4-Me.sub.2 -6-MeO-phenyl                                  910                                                                               CH.sub.3                                                                          c-Pr(Et)CH O 2,6-Cl.sub.2 -4-Me-phenyl                                   911                                                                               CH.sub.3                                                                          c-Pr(Et)CH O 2,4-Cl.sub.2 -phenyl                                        912                                                                               CH.sub.3                                                                          c-Pr(Et)CH O 2-Cl-4-Me-phenyl                                            913                                                                               CH.sub.3                                                                          c-Pr(Et)CH O 2-Me-4-Cl-phenyl                                            914                                                                               CH.sub.3                                                                          c-Pr(Et)CH O 2-NMe.sub.2 -6-Me-pyrid-5-yl                                915                                                                               CH.sub.3                                                                          c-Pr(Et)CH O 2-NMe.sub.2 -4-Me-pyrid-5-yl                                916                                                                               CH.sub.3                                                                          c-Pr(Et)CH O 2-Cl-4-MeO-6-Me-phenyl                                      917                                                                               CH.sub.3                                                                          c-Pr(Et)CH O 2-Cl-4,6-Me.sub.2 -5-F-phenyl                               918                                                                               CH.sub.3                                                                          c-Pr(Et)CH O 6-Cl-2,3-dihydro-benzofuran-5-yl                            919                                                                               CH.sub.3                                                                          c-Pr(Et)CH O 6-Me-2,3-dihydro-benzofuran-5-yl                            920                                                                               CH.sub.3                                                                          c-Pr(n-Pr)CH                                                                              O 2,4,6-Me.sub.3 -phenyl                                      921                                                                               CH.sub.3                                                                          c-Pr(n-Pr)CH                                                                              O 2-Cl-4,6-Me.sub.2 -phenyl                                   922                                                                               CH.sub.3                                                                          c-Pr(n-Pr)CH                                                                              O 2,4-Cl.sub.2 -6-Me-phenyl                                   923                                                                               CH.sub.3                                                                          c-Pr(n-Pr)CH                                                                              O 2,4,6-Cl.sub.3 -phenyl                                      924                                                                               CH.sub.3                                                                          c-Pr(n-Pr)CH                                                                              O 2-Me-4-MeO-phenyl                                           925                                                                               CH.sub.3                                                                          c-Pr(n-Pr)CH                                                                              O 2-Cl-4-MeO-phenyl                                           926                                                                               CH.sub.3                                                                          c-Pr(n-Pr)CH                                                                              O 2,4,6-Me.sub.3 -5-F-phenyl                                  927                                                                               CH.sub.3                                                                          c-Pr(n-Pr)CH                                                                              O 2,5-Me.sub.2 -4-MeO-phenyl                                  928                                                                               CH.sub.3                                                                          c-Pr(n-Pr)CH                                                                              O 2,4-Me.sub.2 -6-MeO-phenyl                                  929                                                                               CH.sub.3                                                                          c-Pr(n-Pr)CH                                                                              O 2,6-Cl.sub.2 -4-Me-phenyl                                   930                                                                               CH.sub.3                                                                          c-Pr(n-Pr)CH                                                                              O 2,4-Cl.sub.2 -phenyl                                        931                                                                               CH.sub.3                                                                          c-Pr(n-Pr)CH                                                                              O 2-Cl-4-Me-phenyl                                            932                                                                               CH.sub.3                                                                          c-Pr(n-Pr)CH                                                                              O 2-Me-4-Cl-phenyl                                            933                                                                               CH.sub.3                                                                          c-Pr(n-Pr)CH                                                                              O 2-NMe.sub.2 -6-Me-pyrid-5-yl                                934                                                                               CH.sub.3                                                                          c-Pr(n-Pr)CH                                                                              O 2-NMe.sub.2 -4-Me-pyrid-5-yl                                935                                                                               CH.sub.3                                                                          c-Pr(n-Pr)CH                                                                              O 2-Cl-4-MeO-6-Me-phenyl                                      936                                                                               CH.sub.3                                                                          c-Pr(n-Pr)CH                                                                              O 2-Cl-4,6-Me.sub.2 -5-F-phenyl                               937                                                                               CH.sub.3                                                                          c-Pr(n-Pr)CH                                                                              O 6-Cl-2,3-dihydro-benzofuran-5-yl                            938                                                                               CH.sub.3                                                                          c-Pr(n-Pr)CH                                                                              O 6-Me-2,3-dihydro-benzofuran-5-yl                            939                                                                               CH.sub.3                                                                          c-Pr(n-Bu)CH                                                                              O 2,4,6-Me.sub.3 -phenyl                                      940                                                                               CH.sub.3                                                                          c-Pr(n-Bu)CH                                                                              O 2-Cl-4,6-Me.sub.2 -phenyl                                   941                                                                               CH.sub.3                                                                          c-Pr(n-Bu)CH                                                                              O 2,4-Cl.sub.2 -6-Me-phenyl                                   942                                                                               CH.sub.3                                                                          c-Pr(n-Bu)CH                                                                              O 2,4,6-Cl.sub.3 -phenyl                                      943                                                                               CH.sub.3                                                                          c-Pr(n-Bu)CH                                                                              O 2-Me-4-MeO-phenyl                                           944                                                                               CH.sub.3                                                                          c-Pr(n-Bu)CH                                                                              O 2-Cl-4-MeO-phenyl                                           945                                                                               CH.sub.3                                                                          c-Pr(n-Bu)CH                                                                              O 2,4,6-Me.sub.3 -5-F-phenyl                                  946                                                                               CH.sub.3                                                                          c-Pr(n-Bu)CH                                                                              O 2,5-Me.sub.2 -4-MeO-phenyl                                  947                                                                               CH.sub.3                                                                          c-Pr(n-Bu)CH                                                                              O 2,4-Me.sub.2 -6-MeO-phenyl                                  948                                                                               CH.sub.3                                                                          c-Pr(n-Bu)CH                                                                              O 2,6-Cl.sub.2 -4-Me-phenyl                                   949                                                                               CH.sub.3                                                                          c-Pr(n-Bu)CH                                                                              O 2,4-Cl.sub.2 -phenyl                                        950                                                                               CH.sub.3                                                                          c-Pr(n-Bu)CH                                                                              O 2-Cl-4-Me-phenyl                                            951                                                                               CH.sub.3                                                                          c-Pr(n-Bu)CH                                                                              O 2-Me-4-Cl-phenyl                                            952                                                                               CH.sub.3                                                                          c-Pr(n-Bu)CH                                                                              O 2-NMe.sub.2 -6-Me-pyrid-5-yl                                953                                                                               CH.sub.3                                                                          c-Pr(n-Bu)CH                                                                              O 2-NMe.sub.2 -4-Me-pyrid-5-yl                                954                                                                               CH.sub.3                                                                          c-Pr(n-Bu)CH                                                                              O 2-Cl-4-MeO-6-Me-phenyl                                      955                                                                               CH.sub.3                                                                          c-Pr(n-Bu)CH                                                                              O 2-Cl-4,6-Me.sub.2 -5-F-phenyl                               956                                                                               CH.sub.3                                                                          c-Pr(n-Bu)CH                                                                              O 6-Cl-2,3-dihydro-benzofuran-5-yl                            957                                                                               CH.sub.3                                                                          c-Pr(n-Bu)CH                                                                              O 6-Me-2,3-dihydro-benzofuran-5-yl                            958                                                                               CH.sub.3                                                                          c-PrCH.sub.2 (Et)CH                                                                       O 2,4,6-Me.sub.3 -phenyl                                      959                                                                               CH.sub.3                                                                          c-PrCH.sub.2 (Et)CH                                                                       O 2-Cl-4,6-Me.sub.2 -phenyl                                   960                                                                               CH.sub.3                                                                          c-PrCH.sub.2 (Et)CH                                                                       O 2,4-Cl.sub.2 -6-Me-phenyl                                   961                                                                               CH.sub.3                                                                          c-PrCH.sub.2 (Et)CH                                                                       O 2,4,6-Cl.sub.3 -phenyl                                      962                                                                               CH.sub.3                                                                          c-PrCH.sub.2 (Et)CH                                                                       O 2-Me-4-MeO-phenyl                                           963                                                                               CH.sub.3                                                                          c-PrCH.sub.2 (Et)CH                                                                       O 2-Cl-4-MeO-phenyl                                           964                                                                               CH.sub.3                                                                          c-PrCH.sub.2 (Et)CH                                                                       O 2,4,6-Me.sub.3 -5-F-phenyl                                  965                                                                               CH.sub.3                                                                          c-PrCH.sub.2 (Et)CH                                                                       O 2,5-Me.sub.2 -4-MeO-phenyl                                  966                                                                               CH.sub.3                                                                          c-PrCH.sub.2 (Et)CH                                                                       O 2,4-Me.sub.2 -6-MeO-phenyl                                  967                                                                               CH.sub.3                                                                          c-PrCH.sub.2 (Et)CH                                                                       O 2,6-Cl.sub.2 -4-Me-phenyl                                   968                                                                               CH.sub.3                                                                          c-PrCH.sub.2 (Et)CH                                                                       O 2,4-Cl.sub.2 -phenyl                                        969                                                                               CH.sub.3                                                                          c-PrCH.sub.2 (Et)CH                                                                       O 2-Cl-4-Me-phenyl                                            970                                                                               CH.sub.3                                                                          c-PrCH.sub.2 (Et)CH                                                                       O 2-Me-4-Cl-phenyl                                            971                                                                               CH.sub.3                                                                          c-PrCH.sub.2 (Et)CH                                                                       O 2-NMe.sub.2 -6-Me-pyrid-5-yl                                972                                                                               CH.sub.3                                                                          c-PrCH.sub.2 (Et)CH                                                                       O 2-NMe.sub.2 -4-Me-pyrid-5-yl                                973                                                                               CH.sub.3                                                                          c-PrCH.sub.2 (Et)CH                                                                       O 2-Cl-4-MeO-6-Me-phenyl                                      974                                                                               CH.sub.3                                                                          c-PrCH.sub.2 (Et)CH                                                                       O 2-Cl-4,6-Me.sub.2 -5-F-phenyl                               975                                                                               CH.sub.3                                                                          c-PrCH.sub.2 (Et)CH                                                                       O 6-Cl-2,3-dihydro-benzofuran-5-yl                            976                                                                               CH.sub.3                                                                          c-PrCH.sub.2 (Et)CH                                                                       O 6-Me-2,3-dihydro-benzofuran-5-yl                            977                                                                               CH.sub.3                                                                          Et.sub.2 CH                                                                               O 2,4-Cl.sub.2 -6-Me-phenyl                                   978                                                                               CH.sub.3                                                                          Et.sub.2 CH                                                                               O 2,4,6-Cl.sub.3 -phenyl                                      979                                                                               CH.sub.3                                                                          Et.sub.2 CH                                                                               O 2-Me-4-MeO-phenyl                                           980                                                                               CH.sub.3                                                                          Et.sub.2 CH                                                                               O 2-Cl-4-MeO-phenyl                                           981                                                                               CH.sub.3                                                                          Et.sub.2 CH                                                                               O 2,4,6-Me.sub.3 -5-F-phenyl                                  982                                                                               CH.sub.3                                                                          Et.sub.2 CH                                                                               O 2,5-Me.sub.2 -4-MeO-phenyl                                  983                                                                               CH.sub.3                                                                          Et.sub.2 CH                                                                               O 2,4-Me.sub.2 -6-MeO-phenyl                                  984                                                                               CH.sub.3                                                                          Et.sub.2 CH                                                                               O 2,6-Cl.sub.2 -4-Me-phenyl                                   985                                                                               CH.sub.3                                                                          Et.sub.2 CH                                                                               O 2,4-Cl.sub.2 -phenyl                                        986                                                                               CH.sub.3                                                                          Et.sub.2 CH                                                                               O 2-Cl-4-Me-phenyl                                            987                                                                               CH.sub.3                                                                          Et.sub.2 CH                                                                               O 2-Me-4-Cl-phenyl                                            988                                                                               CH.sub.3                                                                          Et.sub.2 CH                                                                               O 2-NMe.sub.2 -6-Me-pyrid-5-yl                                989                                                                               CH.sub.3                                                                          Et.sub.2 CH                                                                               O 2-NMe.sub.2 -4-Me-pyrid-5-yl                                990                                                                               CH.sub.3                                                                          Et.sub.2 CH                                                                               O 2-Cl-4,6-Me.sub.2 -5-F-phenyl                               991                                                                               CH.sub.3                                                                          Et.sub.2 CH                                                                               O 6-Cl-2,3-dihydro-benzofuran-5-yl                            992                                                                               CH.sub.3                                                                          Et.sub.2 CH                                                                               O 6-Me-2,3-dihydro-benzofuran-5-yl                            __________________________________________________________________________

Additional compounds, wherein Y=oxygen that can be synthesized using synthetic Scheme 6 or Scheme 7 are listed Table 4

                  TABLE 4                                                          ______________________________________                                          ##STR13##                                                                     Ex.                                                                            No.  R.sup.1 R.sup.3 Y    Ar               mp                                  ______________________________________                                         1000 CH.sub.3                                                                               Et.sub.2 CH                                                                            O    2,4,6-Me.sub.3 -phenyl                               1001 CH.sub.3                                                                               Et.sub.2 CH                                                                            O    2-Cl-4,6-Me.sub.2 -phenyl                            1002 CH.sub.3                                                                               Et.sub.2 CH                                                                            O    2,4-Cl.sub.2 -6-Me-phenyl                            1003 CH.sub.3                                                                               Et.sub.2 CH                                                                            O    2,4,6-Cl.sub.3 -phenyl                               1004 CH.sub.3                                                                               Et.sub.2 CH                                                                            O    2-Me-4-MeO-phenyl                                    1005 CH.sub.3                                                                               Et.sub.2 CH                                                                            O    2-Cl-4-MeO-phenyl                                    1006 CH.sub.3                                                                               Et.sub.2 CH                                                                            O    2,4,6-Me.sub.3 -5-F-phenyl                           1007 CH.sub.3                                                                               Et.sub.2 CH                                                                            O    2,5-Me.sub.2 -4-MeO-phenyl                           1008 CH.sub.3                                                                               Et.sub.2 CH                                                                            O    2,4-Me.sub.2 -6-MeO-phenyl                           1009 CH.sub.3                                                                               Et.sub.2 CH                                                                            O    2,6-Cl.sub.2 -4-Me-phenyl                            1010 CH.sub.3                                                                               Et.sub.2 CH                                                                            O    2,4-Cl.sub.2 -phenyl                                 1011 CH.sub.3                                                                               Et.sub.2 CH                                                                            O    2-Cl-4-Me-phenyl                                     1012 CH.sub.3                                                                               Et.sub.2 CH                                                                            O    2-Me-4-Cl-phenyl                                     1013 CH.sub.3                                                                               Et.sub.2 CH                                                                            O    2-NMe.sub.2 -6-Me-pyrid-5-yl                         1014 CH.sub.3                                                                               Et.sub.2 CH                                                                            O    2-NMe.sub.2 -4-Me-pyrid-5-yl                         1015 CH.sub.3                                                                               Et.sub.2 CH                                                                            O    2-Cl-4-MeO-6-Me-phenyl                               1016 CH.sub.3                                                                               Et.sub.2 CH                                                                            O    2-Cl-4,6-Me.sub.2 -5-F-phenyl                        1017 CH.sub.3                                                                               Et.sub.2 CH                                                                            O    6-Cl-2,3-dihydro-benzofuran-5-yl                     1018 CH.sub.3                                                                               Et.sub.2 CH                                                                            O    6-Me-2,3-dihydro-benzofuran-5-yl                     ______________________________________                                    

Utility CRF-R1 Receptor Binding Assay for the Evaluation of Biological Activity

The following is a description of the isolation of cell membranes containing cloned human CRF-R1 receptors for use in the standard binding assay as well as a description of the assay itself.

Messenger RNA was isolated from human hippocampus. The mRNA was reverse transcribed using oligo (dt) 12-18 and the coding region was amplified by PCR from start to stop codons The resulting PCR fragment was cloned into the EcoRV site of PGEMV, from whence the insert was reclaimed using XhoI+XbaI and cloned into the XhoI+XbaI sites of vector pm3ar (which contains a CMV promoter, the SV40 `t` splice and early poly A signals, an Epstein-Barr viral origin of replication, and a hygromycin selectable marker). The resulting expression vector, called phchCRFR was transfected in 293EBNA cells and cells retaining the episome were selected in the presence of 400 mM hygromycin. Cells surviving 4 weeks of selection in hygromycin were pooled, adapted to growth in suspension and used to generate membranes for the binding assay described below. Individual aliquots containing approximately 1×10⁸ of the suspended cells were then centrifuged to form a pellet and frozen.

For the binding assay a frozen pellet described above containing 293EBNA cells transfected with hCRFR1 receptors is homogenized in 10 ml of ice cold tissue buffer (50 mM HEPES buffer pH 7.0, containing 10 mM MgCl₂, 2 mM EGTA, 1 mg/l aprotinin, 1 mg/ml leupeptin and 1 mg/ml pepstatin). The homogenate is centrifuged at 40,000×g for 12 min and the resulting pellet rehomogenized in 10 ml of tissue buffer. After another centrifugation at 40,000×g for 12 min, the pellet is resuspended to a protein concentration of 360 mg/ml to be used in the assay.

Binding assays are performed in 96 well plates; each well having a 300 ml capacity. To each well is added 50 ml of test drug dilutions (final concentration of drugs range from 10⁻¹⁰ -10⁻⁵ M), 100 ml of ¹²⁵ I-ovine-CRF (¹²⁵ I-o-CRF) (final concentration 150 pM) and 150 ml of the cell homogenate described above. Plates are then allowed to incubate at room temperature for 2 hours before filtering the incubate over GF/F filters (presoaked with 0.3% polyethyleneimine) using an appropriate cell harvester. Filters are rinsed 2 times with ice cold assay buffer before removing individual filters and assessing them for radioactivity on a gamma counter.

Curves of the inhibition of ¹²⁵ I-o-CRF binding to cell membranes at various dilutions of test drug are analyzed by the iterative curve fitting program LIGAND [P. J. Munson and D. Rodbard, Anal. Biochem. 107:220 (1980)], which provides Ki values for inhibition which are then used to assess biological activity.

A compound is considered to be active if it has a K_(i) value of less than about 10000 nM for the inhibition of CRF. Compounds with a K_(i) less than 100 nM for the inhibition of CRF are desirable. A number of compounds of the invention have been made and tested in the above assay and shown to have K_(i) values less than 100 nM thus confirming the utility of the invention.

Inhibition of CRF-Stimulated Adenylate Cyclase Activity

Inhibition of CRF--Stimulated adenylate cyclase activity was performed as described by G. Battaglia et al. Synapse 1:572 (1987). Briefly, assays were carried out at 37° C. for 10 min in 200 ml of buffer containing 100 mM Tris-HCl (pH 7.4 at 37° C.), 10 mM MgCl₂, 0.4 mM EGTA, 0.1% BSA, 1 mM isobutylmethylxanthine (IBMX), 250 units/ml phosphocreatine kinase, 5 mM creatine phosphate, 100 mM guanosine 5'-triphosphate, 100 nM OCRF, antagonist peptides (concentration range 10⁻⁹ to ₁₀ ⁻⁶ m) and 0.8 mg original wet weight tissue (approximately 40-60 mg protein). Reactions were initiated by the addition of 1 mM ATP/[³² P]ATP (approximately 2-4 mCi/tube) and terminated by the addition of 100 ml of 50 mM Tris-HCL, 45 mM ATP and 2% sodium dodecyl sulfate. In order to monitor the recovery of cAMP, 1 μl of [³ H]cAMP (approximately 40,000 dpm) was added to each tube prior to separation. The separation of [³² P]cAMP from [³² P]ATP was performed by sequential elution over Dowex and alumina columns. Recovery was consistently greater than 80%.

A compound of this invention was tested in this assay and found to be active; IC₅₀ <10000 nM.

In vivo Biological Assay

The in vivo activity of the compounds of the present invention can be assessed using any one of the biological assays available and accepted within the art. Illustrative of these tests include the Acoustic Startle Assay, the Stair Climbing Test, and the Chronic Administration Assay. These and other models useful for the testing of compounds of the present invention have been outlined in C. W. Berridge and A. J. Dunn Brain Research Reviews 15:71 (1990)

Compounds may be tested in any species of rodent or small mammal. Disclosure of the assays herein is not intended to limit the enablement of the invention.

Compounds of this invention have utility in the treatment of inbalances associated with abnormal levels of corticotropin releasing factor in patients suffering from depression, affective disorders, and/or anxiety.

Compounds of this invention can be administered to treat these abnormalities by means that produce contact of the active agent with the agent's site of action in the body of a mammal. The compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals either as individual therapeutic agent or in combination of therapeutic agents. They can be administered alone, but will generally be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The dosage administered will vary depending on the use and known factors such as pharmacodynamic character of the particular agent, and its mode and route of administration; the recipient's age, weight, and health; nature and extent of symptoms; kind of concurrent treatment; frequency of treatment; and desired effect. For use in the treatment of said diseases or conditions, the compounds of this invention can be orally administered daily at a dosage of the active ingredient of 0.002 to 200 mg/kg of body weight. Ordinarily, a dose of 0.01 to 10 mg/kg in divided doses one to four times a day, or in sustained release formulation will be effective in obtaining the desired pharmacological effect.

Dosage forms (compositions) suitable for administration contain from about 1 mg to about 100 mg of active ingredient per unit. In these pharmaceutical compositions, the active ingredient will ordinarily be present in an amount of about 0.5 to 95% by weight based on the total weight of the composition.

The active ingredient can be administered orally is solid dosage forms, such as capsules, tablets and powders; or in liquid forms such as elixirs, syrups, and/or suspensions. The compounds of this invention can also be administered parenterally in sterile liquid dose formulations.

Gelatin capsules can be used to contain the active ingredient and a suitable carrier such as but not limited to lactose, starch, magnesium stearate, steric acid, or cellulose derivatives. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of time. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste, or used to protect the active ingredients from the atmosphere, or to allow selective disintegration of the tablet in the gastrointestinal tract.

Liquid dose forms for oral administration can contain coloring or flavoring agents to increase patient acceptance.

In general, water, pharmaceutically acceptable oils, saline, aqueous dextrose (glucose), and related sugar solutions and glycols, such as propylene glycol or polyethylene glycol, are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, butter substances. Antioxidizing agents, such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or in combination, are suitable stabilizing agents. Also used are citric acid and its salts, and EDTA. In addition, parenteral solutions can contain preservatives such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences", A. Osol, a standard reference in the field.

Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:

Capsules

A large number of units capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered active ingredient, 150 mg lactose, 50 mg cellulose, and 6 mg magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestible oil such as soybean, cottonseed oil, or olive oil is prepared and injected by means of a positive displacement was pumped into gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules were washed and dried.

Tablets

A large number of tablets are prepared by conventional procedures so that the dosage unit was 100 mg active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch, and 98.8 mg lactose. Appropriate coatings may be applied to increase palatability or delayed adsorption.

The compounds of this invention may also be used as reagents or standards in the biochemical study of neurological function, dysfunction, and disease. 

We claim:
 1. A compound of Formula I: ##STR14## or a pharmaceutically acceptable salt form thereof, wherein: Z is CR² ;Y is NR⁴, O, S(O)_(n) ; Ar is phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, indolinyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, benzothiazolyl, indazolyl, isoxazolyl or pyrazolyl, each substituted with 0 to 4 R⁵ groups; wherein Ar is attached to Y through an unsaturated carbon; R¹ is H, halo, C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₃ -C₈ cycloalkyl, C₁ -C₄ haloalkyl, aryl, heterocyclyl, --CN, --OR⁷, --SH, --S(O)_(n) R¹³, --COR⁷, --CONR⁶ R⁷, --CO₂ R⁷, --OC(O)R¹³, --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R⁷, or --NR⁶ R⁷, wherein C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl or C₃ -C₈ cycloalkyl is each substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, --CN, --OR⁷, --SH, --S(O)_(n) R¹³, --COR⁷, --CO₂ R⁷, --OC(O)R¹³, --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R⁷, --NR⁶ R⁷, --CONR⁶ R⁷, aryl and heterocyclyl; R² is H, C₁ -C₄ alkyl, C₂ -C₄ alkenyl, C₂ -C₄ alkynyl, C₃ -C₆ cycloalkyl, halo, --CN, C₁ -C₄ haloalkyl, --NR⁹ R¹⁰, --NR⁹ COR¹⁰, --NR⁹ CO₂ R¹⁰, --OR¹¹, --SH or --S(O)_(n) R¹² ; R³ is C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₃ -C₈ cycloalkyl, C₁ -C₄ haloalkyl, aryl, heterocyclyl, --CN, --OR⁷, --S(O)₂ R¹³, --COR⁷, --CO₂ R⁷, --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --CONR⁶ R⁷, --NR⁸ CO₂ R⁷, or --NR⁶ R⁷, wherein C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl or C₃ -C₈ cycloalkyl is each substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, --CN, --OR⁷, --S(O)_(n) R¹³, --COR⁷, --CO₂ R⁷, --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R⁷, --NR⁶ R⁷, --CONR⁶ R⁷, aryl and heterocyclyl, with the proviso that when R³ is aryl, Ar is not imidazolyl; R⁴ is H, C₁ -C₆ alkyl, C₂ -C₆ alkenyl or C₂ -C₆ alkynyl, wherein C₂ -C₆ alkenyl or C₂ -C₆ alkynyl is optionally substituted with C₁ -C₄ alkyl or C₃ -C₆ cycloalkyl and wherein C₁ -C₆ alkyl is optionally substituted with C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, C₁ -C₄ haloalkyl, --OR⁷, --S(O)_(n) R¹², --CO₂ R⁷, --NR⁶ R⁷ or --NR⁹ COR¹⁰ ; R⁵ is independently selected at each occurrence from C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, aryl, heterocyclyl, --NO₂, halo, --CN, C₁ -C₄ haloalkyl, --NR⁶ R⁷, --NR⁸ COR⁷, --NR⁸ CO₂ R⁷, --OR⁷, --COR⁷, --CO₂ R⁷, --CONR⁶ R⁷, --CON(OR⁹)R⁷, --SH, and --S(O)_(n) R¹³,wherein C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₃ -C₆ cycloalkyl and C₄ -C₁₂ cycloalkylalkyl are substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, --NO₂, halo, --CN, --OR⁷, --COR⁷, --CO₂ R⁷, --CONR⁶ R⁷, --NR⁶ R⁷, --NR⁸ COR⁷, --NR⁸ CO.sub.₂ R⁷ and --S(O)_(n) R¹³ ; R⁶ and R⁷ are independently selected at each occurrence from H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, aryl, aryl(C₁ -C₄ alkyl)-, heterocyclyl, heterocyclyl(C₁ -C₄ alkyl)-, morpholinoethyl, morpholinopropyl and morpholinobutyl; or NR⁶ R⁷ taken together as a whole is piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine;wherein C₁ -C₄ alkyl, may be substituted with 0 to 2 substituents independently selected at each occurrence from --OH or C₁ -C₄ alkoxy groups; R⁸ is independently at each occurrence H or C₁ -C₄ alkyl; R⁹ and R¹⁰ are independently at each occurrence selected from H, C₁ -C₄ alkyl and C₃ -C₆ cycloalkyl; R¹¹ is H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, or C₃ -C₆ cycloalkyl; R¹² is C₁ -C₄ alkyl, C₁ -C₄ haloalkyl or --NR⁶ R⁷ ; R¹³ is C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, --NR⁶ R⁷, aryl, aryl(C₁ -C₄ alkyl)-, heterocyclyl or heterocyclyl(C₁ -C₄ alkyl)-; R¹⁴ is C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, --NR¹⁵ R¹⁶ ; R¹⁵ and R¹⁶ are independently selected at each occurrence from H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl and C₄ -C₁₂ cycloalkylalkyl; or --NR¹⁵ R¹⁶ taken together as a whole is piperidine, pyrrolidine, piperazine, N-methyl-piperazine, morpholine or thiomorpholine; aryl is phenyl, biphenyl or naphthyl, each substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, --CN, --OR¹⁵, --SH, --S(O)_(n) R¹⁴, --COR¹⁵, --CO₂ R¹⁵, --OC(O)R¹⁴, --NO₂, --NR⁸ COR¹⁵, --N(COR^(l5))₂, --NR⁸ CONR¹⁵ R¹⁶, --NR⁸ CO₂ R¹⁵, --NR¹⁵ R¹⁶ and --CONR¹⁵ R¹⁶ ; heterocyclyl is pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzthiazolyl, isoxazolyl or pyrazolyl, each substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, --CN, --OR¹⁵, --SH, --S(O)_(n) R¹⁴, --COR¹⁵, --CO₂ R¹⁵, --OC(O)R¹⁴, --NO₂, --NR⁸ COR¹⁵, --N(COR¹⁵)₂, --NR⁸ CONR¹⁵ R¹⁶, --NR⁸ CO₂ R¹⁵, --NR¹⁵ R¹⁶ and --CONR¹⁵ R¹⁶ ; and n is independently at each occurrence 0, 1 or
 2. 2. A compound of claim 1 wherein:Z is CR² ; Y is NR⁴ or O; Ar is phenyl or pyridyl, each substituted with 0 to 4 R⁵ groups; R¹ is H, halo, C₁ -C₄ alkyl, cyclopropyl, C₁ -C₄ haloalkyl, --CN, --NR⁶ R⁷, --CONR⁶ R⁷, --OR⁷, --COR⁷, --CO₂ R⁷ or --S(O)_(n) R¹³,wherein C₁ -C₄ alkyl is substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, halo, --CN, --OR⁷, --S(O)_(n) R¹³, --COR⁷, --CO₂ R⁷, --NR⁸ COR⁷, --NR⁸ CO₂ R⁷, --NR⁶ R⁷ and aryl; R² is H, C₁ -C₄ alkyl, halo, C₁ -C₄ haloalkyl; R³ is C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₃ -C₈ cycloalkyl, C₁ -C₄ haloalkyl, aryl, heterocyclyl, --CN, --OR⁷, --S(O)₂ R¹³, --COR⁷, --CO₂ R⁷, --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --CONR⁶ R⁷, --NR⁸ CO₂ R⁷, or --NR⁶ R⁷,wherein C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl or C₃ -C₈ cycloalkyl is each substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, C₁ -C₄ haloalkyl, halo, --CN, --OR⁷, --S(O)_(n) R¹³, --CO₂ R⁷, --NR⁸ COR⁷, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R⁷, --NR⁶ R⁷, aryl and heterocyclyl; R⁴ is H, C₁ -C₆ alkyl or C₂ -C₆ alkenyl, wherein C₁ -C₆ alkyl is optionally substituted with C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, --OR⁷, --S(O)_(n) R¹², --CO₂ R⁷, --NR⁶ R⁷ or --NR⁹ COR¹⁰ ; R⁵ is independently selected at each occurrence from C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₃ -C₆ cycloalkyl, C₄ -C₈ cycloalkylalkyl, aryl, heterocyclyl, C₁ -C₄ haloalkyl, halo, --CN, --NO₂, --NR⁶ R⁷, --COR⁷, --OR⁷, --CONR⁶ R⁷, --CON (OR⁹) R⁷, CO₂ R⁷ and --S(O)_(n) R¹³,wherein C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₃ -C₆ cycloalkyl and C₄ -C₈ cycloalkylalkyl are substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, --NO₂, halo, --CN, --NR⁶ R⁷, COR⁷, --OR⁷, --CONR⁶ R⁷, CO₂ R⁷ and --S(O)_(n) R¹³ ; R⁶ and R⁷ are independently selected at each occurrence from H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, aryl, aryl(C₁ -C₄ alkyl)-, heterocyclyl, heterocyclyl(C₁ -C₄ alkyl)-, morpholinoethyl, morpholinopropyl and morpholinobutyl; or --NR⁶ R⁷ taken together as a whole is piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine;wherein C₁ -C₄ alkyl, may be substituted with 0 to 2 substituents independently selected at each occurrence from --OH or C₁ -C₄ alkoxy groups; R⁸ is independently at each occurrence H or C₁ -C₄ alkyl; R⁹ and R¹⁰ are independently at each occurrence selected from H, C₁ -C₄ alkyl and C₃ -C₆ cycloalkyl; R¹¹ is H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, or C₃ -C₆ cycloalkyl; R¹² is C₁ -C₄ alkyl, C₁ -C₄ haloalkyl or --NR⁶ R⁷ ; R¹³ is C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, --NR⁶ R⁷, aryl, aryl(C₁ -C₄ alkyl)-, heterocyclyl or heterocyclyl(C₁ -C₄ alkyl)-; R¹⁴ is C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, --NR¹⁵ R¹⁶ ; R¹⁵ and R¹⁶ are independently selected at each occurrence from H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl and C₄ -C₁₂ cycloalkylalkyl; or --NR¹⁵ R¹⁶ taken together as a whole is piperidine, pyrrolidine, piperazine, N-methyl-piperazine, morpholine or thiomorpholine; aryl is phenyl substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, halo, --CN, --OR¹⁵, --S(O)_(n) R¹⁴, --COR¹⁵, --CO₂ R¹⁵, --NO₂, --NR⁸ COR¹⁵, --NR⁸ CONR¹⁵ R¹⁶, --NR⁸ CO₂ R¹⁵ and --NR¹⁵ R¹⁶ ; heterocyclyl is pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, imidazolyl, thiazolyl, pyrrolyl, oxazolyl, isoxazolyl or pyrazolyl, each substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, halo, --CN, --OR¹⁵, --S(O)_(n) R¹⁴, --CO₂ R¹⁵, --NO₂, --NR⁸ COR¹⁵, --NR⁸ CONR¹⁵ R¹⁶, --NR⁸ CO₂ R¹⁵, and --NR¹⁵ R¹⁶ ; and n is independently at each occurrence 0, 1 or
 2. 3. A compound of claim 2 wherein:Z is CR² ; Y is NR⁴ ; Ar is phenyl or pyridyl, each substituted with 0 to 4 R⁵ groups; R¹ is H, halo, C₁ -C₄ alkyl, cyclopropyl, C₁ -C₃ haloalkyl, --CN, --NR⁶ R⁷, --CONR⁶ R⁷, --COR⁷, --CO₂ R⁷, --OR⁷ or --S(O)_(n) R¹³ wherein C₁ -C₄ alkyl is substituted with 0 to 3 substituents independently selected at each occurrence from C₃ -C₄ cycloalkyl, halo, --CN, --OR⁷, --S(O)_(n) R¹³, --COR⁷, --CO₂ R⁷, --NR⁶ R⁷ ; R² is H; R³ is C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₃ -C₆ cycloalkyl, C₁ -C₄ haloalkyl or aryl, wherein C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl or C₃ -C₆ cycloalkyl is each substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, C₁ -C₄ haloalkyl, halo, --CN, --OR⁷, --S(O)_(n) R¹³, --CO₂ R⁷, --NR⁸ COR⁷, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R⁷, --NR⁶ R⁷ and aryl; R⁴ is H, allyl, or C₁ -C₄ alkyl, wherein C₁ -C₄ alkyl is optionally substituted with C₁ -C₄ alkyl, --OR⁷, --S(O)₂ R¹², --CO₂ R⁷, --NR⁶ R⁷ or --NR⁹ COR¹⁰ ; R⁵ is independently selected at each occurrence from C₁ -C₆ alkyl, aryl, heterocyclyl, C₁ -C₄ haloalkyl, halo, --CN, --NO₂, --NR⁶ R⁷, --COR⁷, --OR⁷, --CONR⁶ R⁷, --CON(OR⁹)R⁷, --CO₂ R⁷ and --S(O)_(n) R¹³, wherein C₁ -C₆ alkyl is substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, --NO₂, halo, --CN, --NR⁶ R⁷, COR⁷, --OR⁷, --CONR⁶ R⁷, CO₂ R⁷ and --S(O)_(n) R¹³ ; R⁶ and R⁷ are independently selected at each occurrence from H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl and C₂ -C₈ alkoxyalkyl;wherein C₁ -C₄ alkyl, may be substituted with 0 to 2 substituents independently selected at each occurrence from --OH or C₁ -C₄ alkoxy groups; R⁸, R⁹ and R¹⁰ are independently at each occurrence H or C₁ -C₄ alkyl; R¹² and R¹³ are independently at each occurrence C₁ -C₄ alkyl or --NR⁶ R⁷ ; R¹⁴ is C₁ -C₄ alkyl or --NR¹⁵ R¹⁶ ; R¹⁵ and R¹⁶ are independently at each occurrence H, C₁ -C₄ alkyl or C₂ -C₈ alkoxyalkyl; aryl is phenyl substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, halo, --CN, --OR¹⁵, S(O)_(n) R¹⁴, --COR¹⁵ --CO₂ R¹⁵, --NO₂ and --NR¹⁵ R¹⁶ ; and n is independently at each occurrence 0, 1 or
 2. 4. A compound of claim 3 wherein:Z is CR² ; Y is NR⁴ ; Ar is phenyl or pyridyl, each substituted with 2 to 4 R⁵ groups; R¹ is H, Cl, Br, methyl, ethyl, cyclopropyl, or --CN, R² is H; R³ is C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₃ -C₆ cycloalkyl, C₁ -C₄ haloalkyl or aryl, wherein C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl or C₃ -C₆ cycloalkyl is each substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, --CF₃, halo, --CN, --OR⁷, and aryl; R⁴ is H, methyl, ethyl, i-propyl, n-propyl, n-butyl, i-butyl, s-butyl, n-butyl, or allyl; R⁵ is independently selected at each occurrence from methyl, ethyl, i-propyl, n-propyl, aryl, --CF₃, halo, --CN, --N(CH₃)2, --C(═O)CH₃, --OCH₃, --OCH₂ CH₃, --OCF₃, and --S(O)₂ CH₃ ; R¹⁴ is C₁ -C₄ alkyl or --NR¹⁵ R¹⁶ ; R¹⁵ and R¹⁶ are independently at each occurrence H, C₁ -C₄ alkyl or C₂ -C₈ alkoxyalkyl; aryl is phenyl substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, halo, --CN, --OR¹⁵, --S(O)_(n) R¹⁴, --COR¹⁵, --CO₂ R₅, --NO₂ and --NR¹⁵ R¹⁶ ; and n is independently at each occurrence 0, 1 or
 2. 5. A compound of claim 4 selected from:3-[(2,4-Dibromophenyl)amino]-5-chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone; 3-[[2-Bromo-4-(1-methylethyl)phenyl]amino]-5-chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone; 3-[(2,4-Dibromophenyl)ethylamino]-5-chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone; 3-[[2-Bromo-4-(1-methylethyl)phenyl]ethylamino]-5-chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone; 3-[(2,4,6-Trimethylphenyl)amino]-5-chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone; 3-[(2,4,6-Trimethylphenyl)ethylamino]-5-chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone; (+/-)-3-[(2,4,6-Trimethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2 (1H)-pyrazinone; 3-[(2-Bromo-4,6-dimethoxyphenyl)amino]-5-chloro-1-(1-ethylpropyl)-2(1H)-pyrazinone; 3-[(2-Cyano-4,6-dimethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2 (1H)-pyrazinone; (+/-)-3-[(2-Bromo-4,6-dimethoxyphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2 (1H)-pyrazinone; (+/-)-3-[(2-chloro-4,6-dimethoxyphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2 (1H)-pyrazinone; (+/-)-3-[(4,6-Dimethyl-2-iodophenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2 (1H)-pyrazinone; [(2-cyano-4,6-dimethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone; (+/-)-3-[(2-Bromo-4,6-dimethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2 (1H)-pyrazinone; (+/-)-3-[(4-Bromo-2,6-dimethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone; (+/-)-3-[(4-Acetyl-2,6-dimethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2 (1H)-pyrazinone; (+/-)-3-[(2-Acetyl-4,6-dimethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone; (+/-)-3-[(4,6-Dimethyl-2-thiomethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone; (+/-)-3-[(4,6-Dimethyl-2-methylsulfonylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone; (+/-)-3-[(4-chloro-2-iodo-6-methylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone; 3-[(2,4,6-Trimethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; 3-[(2,4,6-Trimethylphenyl)amino]-5-chloro-1-phenyl-2(1H)-pyrazinone; (+/-)-3-[(2,4-Dibromophenyl)amino]-5-methyl-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone; (+/-)-3-[[2-Bromo-4-(1-methylethyl)phenyl]amino]-5-methyl-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone; (+/-)-3-[(2,4,6-Trimethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone; 3-[(2,4,6-Trimethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; 3-[(2,4-Dichloro-6-methylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; 3-[(2,4-Dichloro-6-methylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; 3-[(2,4-Dibromo-6-methylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; (+/-)-3-[(2,4,6-Trimethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone; (+/-)-3-[(2,4,6-Trimethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone; 3-[(2,4,6-Trimethylphenyl)amino]-5-chloro-1-[1-(2-methoxyethyl)-3-methoxypropyl]-2(1H)-pyrazinone; (+/-)-3-[(2,4-Dimethyl-6-methoxyphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone; (+/-)-3-[(2,4-Dimethyl-6-methoxyphenyl)amino]-5-chloro-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone; (+/-)-3-[(2,4-Dimethyl-6-methoxyphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone; (+/-)-3-[(4-Bromo-2,6-dimethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone; (+/-)-3-[(2-chloro-4,6-dimethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone; (+/-)-3-[[2,4-Dimethyl-6-(methoxymethyl)phenyl]amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone; 3-[(2,4-Dimethyl-6-methoxyphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; 3-[(4-Bromo-2,6-dimethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; 3-[(2-chloro-4,6-dimethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; 3-[[2,4-Dimethyl-6-(methoxymethyl)phenyl]amino]-5-methyl-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; (+/-)-3-[(2,4-Dimethyl-6-methoxyphenyl)amino]-5-chloro-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone; (+/-)-3-[(4-Bromo-2,6-dimethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone; (+/-)-3-[(2-chloro-4,6-dimethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone; (+/-)-3-[[2,4-Dimethyl-6-(methoxymethyl)phenyl]amino]-5-chloro-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone; 3-[(2,4-Dimethyl-6-methoxyphenyl)amino]-5-chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; 3-[(4-Bromo-2,6-dimethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; 3-[(2-chloro-4,6-dimethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; 3-[[2,4-Dimethyl-6-(methoxymethyl)phenyl]amino]-5-chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; (+/-)3-[(2,4-Dimethyl-6-methoxyphenyl)amino]-5-chloro-1-(2-methoxy-1-methylethyl)-2(1H)-pyrazinone; (+/-)3-[(4-Bromo-2,6-dimethylphenyl)amino]-5-chloro-1-(2-methoxy-1-methylethyl)-2(1H)-pyrazinone; (+/-)3-[(4-Bromo-2,6-dimethylphenyl)amino]-5-chloro-1-[1-(ethoxymethyl)propyl]-2(1H)-pyrazinone; (+/-)3-[(4-Bromo-2,6-dimethylphenyl)amino]-5-chloro-1-(2-ethoxy-1-methylethyl)-2(1H)-pyrazinone; and (+/-)3-[(4-Bromo-2,6-difluorophenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone; (+/-)-3-[(2-Bromo-4,6-dimethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H) pyrazinone; (+/-)-3-[(2,4-Dimethyl-6-thiomethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone; (+/-)-3-[(2,4-Dimethyl-6-methylsulfonylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone; (+/-)-3-[(2,6-Dimethyl-4-(N,N-dimethylamino)phenyl)-amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone; (+/-)-3-[(2,4-Dichloro-6-methylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone; (+/-)-3-[(4-chloro-2,6-dimethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone; (+/-)-3-[(2,6-Dimethyl-4-thiomethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone; (+/-)-3-[(2,6-Dimethyl-4-methoxyphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone; (+/-)-3-[(2,6-Dimethyl-4-methylsulfonylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone; (+/-)-3-[(4-Acetyl-2,6-dimethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-3-methoxypropyl]-2(1H)-pyrazinone; 3-[(4-Bromo-2,6-dimethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; 3-[(4-Acetyl-2,6-dimethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; 3-[(2,6-Dimethyl-4-thiomethylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; 3-[(2,6-Dimethyl-4-methylsulfonylphenyl)amino]-5-methyl-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; 3-[(2,6-Dimethyl-4-(N,N-dimethylamino)phenyl)amino]-5-methyl-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; 3-[(4,6-Dimethyl-2-(N,N-dimethylamino)phenyl)amino]-5-methyl-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; (+/-)3-[(2,6-Dimethyl-4-thiomethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone; (+/-)3-[(2,6-Dimethyl-4-methylsulfonylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone; (+/-)3-[(2-chloro-4,6-dimethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone; (+/-)3-[(4-Bromo-6-methoxy-2-methylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone; 3-[(2,6-Dimethyl-4-thiomethylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; 3-[(2,6-Dimethyl-4-methylsulfonylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; 3-[(4-Bromo-6-methoxy-2-methylphenyl)amino]-5-chloro-1-[1-(methoxymethyl)-2-methoxyethyl]-2(1H)-pyrazinone; and 3-[(2,4,6-Trimethylphenyl)amino]-5-methyl-1-(1-ethylpropyl)-2(1H)-pyrazinone.6.
 6. A compound of claim 1 wherein:Z is CR² ; Y is NR⁴ or O; Ar is phenyl or pyridyl, each substituted with 0 to 4 R⁵ groups; R¹ is H, halo, C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₃ -C₈ cycloalkyl, C₁ -C₄ haloalkyl, aryl, heterocyclyl, --CN, --OR⁷, --SH, --S(O)_(n) R¹³, --COR⁷, --CONR⁶ R⁷, --CO₂ R⁷, --OC(O)R¹³, --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R⁷, or --NR⁶ R⁷,wherein C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl or C₃ -C₈ cycloalkyl is each substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, --CN, --OR⁷, --SH, --S(O)_(n) R¹³, --COR⁷ ₁ --CO₂ R⁷, --OC(O)R¹³, --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R⁷, --NR⁶ R⁷, --CONR⁶ R⁷, aryl and heterocyclyl; R² is H, C₁ -C₄ alkyl, halo, C₁ -C₄ haloalkyl; R³ is C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, C₁ -C₄ haloalkyl and --NR⁶ R⁷,wherein C₁ -C₄ alkyl is substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, C₁ -C₄ haloalkyl, halo, --CN, --OR⁷, --S(O)_(n) R^(l3), --COR⁷, --CO₂ R⁷, --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R⁷, --NR⁶ R⁷ and --CONR⁶ R⁷ ; R⁴ is H, C₁ -C₆ alkyl or C₂ -C₆ alkenyl, wherein C₁ -C₆ alkyl is optionally substituted with C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, --OR⁷, --S(O)_(n) R¹², --CO₂ R⁷, --NR⁶ R⁷ or --NR⁹ COR¹⁰ ; R⁵ is independently selected at each occurrence from C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, aryl, heterocyclyl, --NO₂, halo, --CN, C₁ -C₄ haloalkyl, --NR⁶ R⁷, --NR⁸ COR⁷, --NR⁸ CO₂ R⁷, --OR⁷, --COR⁷, --CO₂ R⁷, --CONR⁶ R⁷, --CON(OR⁹)R⁷ and --S(O)_(n) R¹³, wherein C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₃ -C₆ cycloalkyl and C₄ -C₁₂ cycloalkylalkyl are substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, --NO₂, halo, --CN, --OR⁷, --COR⁷, --CO₂ R⁷, --CONR⁶ R⁷, --NR⁶ R⁷, --NR⁸ COR⁷, --NR⁸ CO₂ R⁷ and --S(O)_(n) R¹³ ; R⁶ and R⁷ are independently selected at each occurrence from H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, aryl, aryl(C₁ -C₄ alkyl)-, heterocyclyl, heterocyclyl (C₁ -C₄ alkyl)-, morpholinoethyl, morpholinopropyl and morpholinobutyl; or --NR⁶ R⁷ taken together as a whole is piperidine, pyrrolidine, piperazine, N-methyl-piperazine, morpholine or thiomorpholine;wherein C₁ -C₄ alkyl, may be substituted with 0 to 2 substituents independently selected at each occurrence from --OH or C₁ -C₄ alkoxy groups; R⁸ is independently at each occurrence H or C₁ -C₄ alkyl; R⁹ and R¹⁰ are independently at each occurrence selected from H, C₁ -C₄ alkyl and C₃ -C₆ cycloalkyl; R¹¹ is H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, or C₃ -C₆ cycloalkyl; R¹² is C₁ -C₄ alkyl, C₁ -C₄ haloalkyl or --NR⁶ R⁷ ; R¹³ is C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, --NR⁶ R⁷, aryl, aryl(C₁ -C₄ alkyl)-, heterocyclyl or heterocyclyl(C₁ -C₄ alkyl)-; R¹⁴ is C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, --NR¹⁵ R¹⁶ ; R¹⁵ and R¹⁶ are independently selected at each occurrence from H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl and C₄ -C₁₂ cycloalkylalkyl; or --NR¹⁵ R¹⁶ taken together as a whole is piperidine, pyrrolidine, piperazine, N-methyl-piperazine, morpholine or thiomorpholine; aryl is phenyl or naphthyl, each substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, halo, --CN, --OR¹⁵, --S(O)_(n) R¹⁴, --COR¹⁵, --CO₂ R¹⁵, --NO₂, --NR⁸ COR¹⁵, --NR⁸ CONR¹⁵ R¹⁶, --NR⁸ CO₂ R¹⁵ and --NR¹⁵ R¹⁶ ; heterocyclyl is pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, imidazolyl, thiazolyl, pyrrolyl, oxazolyl, isoxazolyl or pyrazolyl, each substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, halo, --CN, --OR¹⁵, --S(O)_(n) R¹⁴, --CO₂ R¹⁵, --NO₂, --NR⁸ COR¹⁵, --NR⁸ CONR¹⁵ R¹⁶, --NR⁸ CO₂ R¹⁵, and --NR¹⁵ R¹⁶ ; and n is independently at each occurrence 0, 1 or
 2. 7. A compound of claim 6 wherein:Z is CR² ; Y is NR⁴ ; Ar is phenyl or pyridyl, each substituted with 0 to 4 R⁵ groups; R¹ is H, halo, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₃ -C₆ cycloalkyl, C₁ -C₄ haloalkyl, aryl, heterocyclyl, --CN, --OR⁷, --S(O)_(n) R¹³, --COR⁷, --CONR⁶ R⁷, --CO₂ R⁷ or --NR⁶ R⁷,wherein C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl or C₃ -C₆ cycloalkyl is each substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, --CN, --OR⁷, --SH, --S(O)_(n) R¹³, --COR⁷, --CO₂ R⁷, --OC(O)R¹³, --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R⁷, --NR⁶ R⁷, --CONR⁶ R⁷, aryl and heterocyclyl; R² is H; R³ is C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, C₁ -C₄ haloalkyl and --NR⁶ R⁷,wherein C₁ -C₄ alkyl is substituted with 0 to 3 substituents independently selected at each occurrence from C₃ -C₆ cycloalkyl, C₁ -C₄ haloalkyl, halo, --CN, --OR⁷, --S(O)_(n) R¹³, --COR⁷, --CO₂ R⁷, --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R⁷ --NR⁶ R⁷ and --CONR⁶ R⁷ ; R⁴ is H, allyl, or C₁ -C₄ alkyl, wherein C₁ -C₄ alkyl is optionally substituted with C₁ -C₄ alkyl, --OR⁷, --S(O)₂ R¹², --CO₂ R⁷, --NR⁶ R⁷ or --NR⁹ COR¹⁰ ; R⁵ is independently selected at each occurrence from C₁ -C₆ alkyl, aryl, heterocyclyl, C₁ -C₄ haloalkyl, halo, --CN, --NO₂, --NR⁶ R⁷, --COR⁷, --OR⁷, --CONR⁶ R⁷, --CON(OR⁹)R⁷, --CO₂ R⁷ and --S(O)_(n) R^(l3), wherein C₁ -C₆ alkyl is substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, --NO₂, halo, --CN, --NR⁶ R⁷, COR⁷, --OR⁷, --CONR⁶ R⁷, CO₂ R⁷ and --S(O)_(n) R¹³ ; R⁶ and R⁷ are independently selected at each occurrence from H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl and C₂ -C₈ alkoxyalkyl;wherein C₁ -C₄ alkyl, may be substituted with 0 to 2 substituents independently selected at each occurrence from --OH or C₁ -C₄ alkoxy groups; R⁸, R⁹ and R¹⁰ are independently at each occurrence H or C₁ -C₄ alkyl; R¹² and R¹³ are independently at each occurrence C₁ -C₄ alkyl or --NR⁶ R⁷ ; R¹⁴ is C₁ -C₄ alkyl or --NR¹⁵ R¹⁶ ; R¹⁵ and R¹⁶ are independently at each occurrence H, C₁ -C₄ alkyl or C₂ -C₈ alkoxyalkyl; aryl is phenyl substituted with 0 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, halo, --CN, --OR¹⁵, --S(O)_(n) R¹⁴, --COR¹⁵, --CO₂ R¹⁵, --NO₂ and --NR¹⁵ R¹⁶ ; and n is independently at each occurrence 0, 1 or
 2. 8. A method for treating anxiety in a mammal in need of such treatment comprising administering to the mammal a therapeutically effective amount of a compound having a composition of claim
 1. 9. A method for treating anxiety in a mammal in need of such treatment comprising administering to the mammal a therapeutically effective amount of a compound having a composition of claim
 2. 10. A method for treating anxiety in a mammal in need of such treatment comprising administering to the mammal a therapeutically effective amount of a compound having a composition of claim
 3. 11. A method for treating anxiety in a mammal in need of such treatment comprising administering to the mammal a therapeutically effective amount of a compound having a composition of claim
 4. 12. A method for treating anxiety in a mammal in need of such treatment comprising administering to the mammal a therapeutically effective amount of a compound having a composition of claim
 5. 13. A method for treating anxiety in a mammal in need of such treatment comprising administering to the mammal a therapeutically effective amount of a compound having a composition of claim
 6. 14. A method for treating anxiety in a mammal in need of such treatment comprising administering to the mammal a therapeutically effective amount of a compound having a composition of claim
 7. 15. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound having a composition of claim
 1. 16. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound having a composition of claim
 2. 17. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound having a composition of claim
 3. 18. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound having a composition of claim
 4. 19. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound having a composition of claim
 5. 20. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound having a composition of claim
 6. 21. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound having a composition of claim
 7. 22. A method for treating depression in a mammal in need of such treatment comprising administering to the mammal a therapeutically effective amount of a compound having a composition of claim
 1. 23. A method for treating depression in a mammal in need of such treatment comprising administering to the mammal a therapeutically effective amount of a compound having a composition of claim
 2. 24. A method for treating depression in a mammal in need of such treatment comprising administering to the mammal a therapeutically effective amount of a compound having a composition of claim
 3. 25. A method for treating depression in a mammal in need of such treatment comprising administering to the mammal a therapeutically effective amount of a compound having a composition of claim
 4. 26. A method for treating depression in a mammal in need of such treatment comprising administering to the mammal a therapeutically effective amount of a compound having a composition of claim
 5. 27. A method for treating depression in a mammal in need of such treatment comprising administering to the mammal a therapeutically effective amount of a compound having a composition of claim
 6. 28. A method for treating depression in a mammal in need of such treatment comprising administering to the mammal a therapeutically effective amount of a compound having a composition of claim
 7. 